A Crisis in Epidemic Research
About 75 percent of new human diseases are caused by microbes that originate in animals. These include HIV and AIDS, influenzas (including pandemic H1N1, H5N1 and H7N9), Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome-Coronavirus (MERS-CoV), Ebola, Marburg, and Nipah. Several of these have spread extensively in human populations to cause a global epidemic (also known as a pandemic). Population growth and expanded interactions between people, animals, and the environment over the coming decades are expected to increase the spillover of new disease threats from animals to people.
Scientists are largely in the dark about how to stop or treat the many never-seen-before global health problems of recent years, from the emergence of the deadly MERS virus in Saudi Arabia, to a new killer strain of bird flu in China and an unprecedented Ebola outbreak in West Africa. They have been unable to even determine where they came from. In part, that is because vital studies to analyze transmission routes and test experimental drugs or vaccines have simply not been done during epidemics, disease experts say. It is a failure of science, they say, that should not be allowed to happen again.
“Research in all of the epidemics we have faced over the past decade has been woeful,” said Jeremy Farrar, director of the Wellcome Trust global health foundation and an expert on infectious diseases. “The world is at risk because there are huge gaps in our knowledge base. We don’t now have a vaccine for SARS if it came back tomorrow; we don’t know how to treat MERS; it took us six to nine months before we started clinical trials of vaccines for Ebola and in the meantime almost 12,000 people lost their lives; and during the H1N1 pandemic, the number of people randomized into clinical studies was very close to zero.”
Factors Impeding Responsive Epidemic Research
Bureaucracy, logistics and lack of forethought are key factors in the problem, according to Trudie Lang, professor of Global Health Research at Oxford University who has been working on ways to lower such barriers. During the Ebola outbreak that swept through Guinea, Liberia and Sierra Leone, Lang’s team, which specializes in planning and operating trials in vulnerable populations in difficult settings, was tasked with setting up a clinical study of a potential Ebola treatment called brincidofovir. According to Lang, it normally takes 18 months to set up a trial. Her team did it in 16 weeks. However, she admitted that they were still behind the curve.
In the 2009 H1N1 swine flu pandemic, when many governments had stockpiled antiviral drugs such as Roche’s Tamiflu and GlaxoSmithKline’s Relenza and doctors prescribed them, often as a preventative measure without a confirmed diagnosis, no proper randomized clinical trials were conducted to find out for sure whether they helped. This has left health officials with little or no concrete evidence on which to base treatment decisions when the next pandemic flu strain threatens the world.
“It is a huge pity we haven’t made the most of our opportunity to generate evidence,” said Chris Butler, a clinical professor at Cardiff University’s Institute of Primary Care & Public Health, who is now working on the European-wide winter flu trial he hopes will help plug the evidence gap.
There is little doubt that launching clinical trials in an outbreak is fraught with difficulty, partly because a new or rare strain of disease can infect so many and overwhelm health services and partly because there are many bureaucratic hurdles.
Lang’s team was awarded funds in September 2014 and by January 2015 were able to start the trial, but this coincided with a sharp drop in the number of patients with Ebola as the West Africa outbreak was beginning to plateau. Scientists point to vast amounts of form filling, box ticking, contract drafting, committee meeting and agreement signing that are involved in setting up a clinical trial. There is a myriad of permissions required and it can be a Byzantine process taking months to complete.
Legal agreements are needed between the suppliers of the product — the experimental drug, vaccine or other intervention — and the people running the trial, the funding group and the hospitals, clinics or health centers where patients will be recruited. In an infectious disease outbreak scenario, particularly a fast-moving one like with flu or Ebola, these legal issues can be compounded by competition for access to patients.
During the Ebola epidemic for example, Lang says, there were five or six different research groups seeking to set up and run clinical trials in the three most affected countries, each of which already had limited health systems that had been overwhelmed and crushed by the outbreak. “It was ludicrous,” she said. “Because essentially we all had to fight over the same patients. It was like a land grab, and by that time the new cases were going down.”
Preparing for the Next Epidemic
Part of the threat of any disease outbreak, be it Ebola in Africa, the 2003 outbreak of Severe Acute Respiratory Syndrome (SARS) epidemic, Middle East Respiratory Syndrome (MERS) in Saudi Arabia or the new H7N9 bird flu in China, is the unknown. Yet Lang and others contend there is nothing to say the sorts of clinical trials needed in an epidemic cannot largely be drawn up, agreed, signed and sealed ahead of time.
“We need to have protocols ready to go, we need to have a task force of research staff in each region on standby to be deployed into the next outbreak trials,” she said. Legal contracts, for instance, cover broadly the same things for any trial — data sharing and storage, patient confidentiality, informed consent, the timing and publication of results, and the pricing, production and availability of the product if and when it proves useful.
And in a rapidly moving outbreak which may be too swift and deadly to allow for months of organization, a coordinated approach would overcome the problem of having multiple research groups with not enough patients. This would be both scientifically and ethically preferable, according to Lang, since if a trial has to be stopped because it runs out of participants with the relevant disease, then everyone who has taken part until then has run a needless risk.