The treatment of the two Americans with an experimental drug after catching Ebola in West Africa has raised all sorts of ethical implications that will be addressed by a meeting of experts convened by the World Health Organisation next week.
Neat scientific tricks
Since the Ebola outbreak began in February more than 900 people have died. There are no antiviral drugs – the only treatment is with fluid and other supportive measures. Zmapp, the drug given to the two US doctors, is a cocktail of monoclonal antibodies that incorporates some neat scientific tricks that bring together human, mouse, and plant biology.
The antibodies are made by infecting a mouse with Ebola virus, and then isolating the immune cells; each of these produces a specific antibody protein against part of the virus. The one cell that produces the best antibody is grown up into a group of identical cells, called a clone, which is why the drug is said to be “monoclonal”.
Although they are effective at neutralising the virus, these antibodies have to be modified, or “humanised”, so that they are similar to human antibodies and can work with the human immune system. These changes are made by altering the DNA of the genes which produce the antibody proteins. These genes are then injected into a tobacco plant, Nicotiana, which subsequently produces large amounts of the antibody protein.
So far in experiments the drug has shown some effects against Ebola when used to treat infected monkeys. Normally further drug development for humans would take years but in emergency situations like this when the death rate from a disease is especially high, drugs can be used on a compassionate basis without the full set of supporting data.
No conspiracy here
So why was the drug available for the two Americans, but not for any of the hundreds of Africans that have already died? The internet is full of conspiracy theories and outrage, but the truth is a lot less exciting. Those responsible for the Americans simply heard about the drugs, and convinced the developers, themselves, and the two patients involved that it was worth the risk of trying them, even though they had never been used before. The Nigerian authorities have been told that because such small quantities of the drug exist currently, it will not be available for widespread use in Africa.
One of the main problems in controlling the Ebola outbreak in Africa has been convincing poorly educated villagers to follow the tried-and-tested approaches that we know definitely help, namely isolation and fluid treatment. As researchers from our institute in Liverpool have found during this outbreak, people are anxious, and frightened; they are mistrustful of the strangers dressed in space suits who take their loved ones away, don’t allow them to visit and don’t even allow them to see the body once they have died. Imagine if scientists had also wanted to also give them an experimental treatment never before used in humans. There would have been even more chaos.
The medical and scientific communities have been criticised in the past for trialling HIV drugs in Africa that had not been used in the West. The accusation that Africans are just used as guinea pigs to test drugs for Western benefit is too easy to make.
Trialling new drugs
The two American patients appear to have improved on the drug, but it is impossible to know whether this is because of the drug itself, or because they were going to improve anyway. Controlled trials, where half the patients get the drug, and half get a placebo, called Phase III studies, are needed to determine whether any new drug is effective.
Sadly, the scientific and medical communities have failed to conduct any such trials for Ebola, despite the fact that there are several drugs in development, and promising treatments have been used on a compassionate basis before.
However, those who attack the pharmaceutical industry for their “selfishness” are missing the point. No drug company would, in isolation, invest millions of pounds in developing a drug which might be only be needed every few years for a few hundred of the world’s poorest people. Instead a concerted effort is needed to develop partnerships which link academics, industry, African governments, and the major funding agencies. Such approaches have worked in the past for malaria and HIV.
Even with financial investment, taking Ebola drugs forward will be challenging. The normal steps for drug development include early testing in healthy volunteers to look for side effects, then dose-optimising studies, before finally seeing if the drug is really effective. All of this occurs in a highly regulated fashion, which makes even the most simple trial of a well-known drug in a common disease extraordinarily laboured and expensive.
For an unpredictable sporadic disease, with high mortality rates, we need a flexible approach to our clinical trials framework that cuts through some of the normal regulatory hurdles. Why worry about minor side effects in healthy volunteers, if the drug is to be given to those who will die without it? Why waste time on dose-finding studies when people need the highest dose possible, today? We have to stop applying the over-laboured regulation that characterises routine clinical trials to emergency outbreak situations where they are just not appropriate.
Many years ago I led a study to try a new anti-viral treatment for another dangerous emerging infection – the mosquitoes-borne brain disease Japanese encephalitis. We established the trial in a few weeks, at almost no cost beyond the drug itself, and completed the study over the subsequent months. In today’s inappropriately regulated environment such research would simply not be possible.
The current Ebola outbreak is devastating for those affected, and worrying for the rest of society. But if it focuses minds on developing new drugs and vaccines, and establishes a new regime for how we do this, then some long-term benefit may come to everyone, including the most vulnerable in Africa.
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