When we think about preparing for pandemics, we think about vaccines, stockpiles of drugs, and surveillance. We rarely think about research. This oversight means that when big epidemics hit, like the swine flu pandemic of 2009, scientists lose valuable chances to find more about these illnesses. A new consortium is out to change that. I wrote about their work, and the problem of slow clinical research in a new feature for the BMJ, which I’m reprinting here.
While viruses are fast and adaptable, clinical research is lumbering and cumbersome. Epidemics tend to arrive with little warning, spread quickly, and end abruptly. By contrast, clinical trials can take months to plan. Forms must be designed to record the right data and ethical approval must be sought. By the time would-be researchers can vault over these obstacles the epidemic is history. This explains why, during the 2009 A/H1N1 influenza pandemic, virtually no patients were enrolled in a randomised controlled trial designed to identify the best ways of treating the infection.
Such trials are the gold standard of medicine and the best way of getting rigorous evidence for a treatment’s effectiveness. During the pandemic millions of people were treated with the front line drug oseltamivir (Tamiflu). But the only evidence that oseltamivir actually saved lives came from retrospective observational studies, with all the biases they entail. To this date, serious questions remain about the drug’s effectiveness. “A Tamiflu trial during the last pandemic would have resolved all the controversy over whether it works or not,” says Mike Clarke, Director of the UK Cochrane Centre.
In the UK people could request doses of the drug through an NHS hotline. “On the first day of that system, 5000 people received Tamiflu. On that day alone, you could have conducted the biggest trial in the world ever,” says Carl Heneghan from the University of Oxford.Tamiflu’s relatives, zanamivir and peramivir, are similarly mysterious. Are they actually effective against the pandemic strain? What are their ideal doses? Should a high loading dose be used at the start of treatment? Can they be used in combination? Are they suitable for the groups who seem to experience the most severe infections, such as obese people, pregnant women, infants, or those with other diseases? We do not know the answers to these questions, and our ignorance is all the more galling because the virus infected between 11 and 21% of the world’s population.
The same questions dog the many other treatments that doctors turned to during the pandemic, such as steroid hormones, immunoglobulin antibodies, and transfusions of plasma from patients who had fought off the virus. Several thousand patients had such severe problems with their hearts and lungs that doctors had to divert their blood out of their bodies and perfuse it with oxygen by machine—a last ditch treatment known as extracorporeal membrane oxygenation. Each measure has at least one report claiming that it is effective, but these reports are always based on small non-randomised studies. Randomised controlled trials were nowhere to be seen.
“Disgrace is too strong a word, but it’s a shame that we don’t know the answers to these questions after this disease has been through not just poor countries but ours,” says Jeremy Farrar, professor of tropical medicine at Oxford University, who studies infectious diseases in Vietnam. “So much of the world’s population saw this virus.” These problems are not restricted to pandemic flu: the same barriers have held back our knowledge of other infections.
If severe acute respiratory syndrome (SARS) sprang up today, doctors would still ask questions about whether to give patients steroids, immunoglobulins, or ribavirin. And with the sluggish speed of clinical research, they would neither have the answers, nor be in a position to get them.
“Let’s say they announce cases of SARS in Vietnam today,” says Piero Olliaro from the World Health Organization, “can we start doing a study? No. Our response is very poor.” “We don’t ever make the progress we should,” says Farrar. “If a patient comes in tonight with Nipah virus, we can’t look at research done five years ago and say, ‘Look, we should treat this individual in this way.’ Those people would be subject to all sorts of bizarre treatments and we don’t know if they’d work or not.”
Some scientists have had enough. Farrar and others have joined forces to create a global alliance called the International Severe Acute Respiratory Infection Consortium (ISARIC), which will ensure that scientists can carry out effective clinical research during future epidemics. Formally announced in December 2011, ISARIC already includes between 50 and 60 research networks across six continents, and it is still growing. Its supporters include a who’s who of big medical funding agencies: the Wellcome Trust, the UK Medical Research Council, the Bill and Melinda Gates Foundation, Institut National de la Santé et de la Recherche Médicale (Inserm), the Li Ka Shing–University of Oxford Global Health Programme, and the Singapore Ministry of Health.
ISARIC’s goal is to set up relationships, protocols, and strategies during this peacetime period, so that researchers can hit the ground running when the next major infection emerges. When people talk about preparing for epidemics they usually refer to monitoring potential threats or stockpiling drugs and vaccines. ISARIC will deal with the crucial missing element: it will prepare to study epidemics as they happen. Everything from personnel to ethical approval will be readied beforehand, so that when the time comes research can progress at the pace of the virus. Perhaps the most striking aspect of ISARIC is that it is only now being set up.
The last pandemic was preceded by decades of concern about flu, but the preparation focused on epidemiology, modelling, and public health approaches. There was plenty of time to prepare ready made trials, but none was set up. Heneghan thinks that this complacency was partly driven by an inflated sense of certainty about treatments, despite a weak evidence base.
“Some people still think we should just use existing treatments when we have influenza, and that’s just what we do,” he says. “Some people just don’t think into the future enough,” says Clarke. “It’s very surprising that we haven’t got off the shelf trials for major incidents that you know are going to happen.” Farrar adds, “I think nobody thought of [doing this]. If they did, they probably concluded that funding agencies would not fund something that was designed for an uncommon event that would occur at [an] unpredictable time in the future.”
If such reticence once existed this is now changing. In the UK, the National Institute for Health Research (NIHR) put out a call for research proposals in the spring of 2009, as the pandemic was emerging. Despite a fast turnaround, those studies only started after the main waves of infection had passed. Fast was not fast enough.
So in October 2011 the NIHR agreed to fund eight projects, including several clinical studies, which will be activated if another pandemic reaches the UK. Steve Goodacre from the University of Sheffield, who chaired the meeting that funded these proposals , says, “You’d get ethics and regulatory approval, pilot the project, develop data collection forms, set up everything ready to go, and put it on hold until a pandemic happened.” At that point full funding would be released, and the pre-cocked starting pistol would fire. Clarke is involved with one of the funded trials, which will assess the use of low dose steroids as treatments for pandemic flu.
“It’s ready to go when someone says start,” he says. “The UK may be ahead of the game here.” ISARIC, which is collaborating with many of the investigators funded by the NIHR, will extend the same principles worldwide. Its first seeds were planted in November 2010, three months after the H1N1 pandemic had officially come to an end. In its aftermath several biomedical funding organisations, including the Bill and Melinda Gates Foundation, the Wellcome Trust, Institut Pasteur, and the National Institute of Allergy and Infectious Diseases, gathered in Bethesda, Maryland to discuss gaps in research on influenza and other respiratory diseases.
The problem of slow research response stood out. The Wellcome Trust followed up with a meeting to discuss the problem in February 2011. Representatives from 20 clinical networks gathered in London, along with funding agencies, and public health workers from WHO, the US Centers for Disease Control and Prevention (CDC), and more. They all recognised the same problem and agreed to work together to solve it.
“There was a dramatic, enthusiastic endorsement,” recalls Fred Hayden from the Wellcome Trust. “There was a lot of commitment even then.” ISARIC was born. The consortium has since grown in size, and there are currently no restrictions as to the number of networks that can join. ISARIC has won two years of funding, amounting to around £500<thin>000, to set their ambitious plans in motion. But, despite the enthusiasm around the consortium, its members recognise that speeding up the pace of clinical research is a significant challenge.
Even the simple business of recording a patient’s details becomes tricky. You need to decide how to diagnose someone as a case so that you end up with the right sample. You need to work out the criteria on which to include or exclude a patient from a trial. You must decide what research questions to ask so that you know what information to record. Creating these case record forms already takes a lot of time, and there’s more still to be done. Once a research plan has been nailed down it can take months to get funding and ethical approval, at a time when responses are needed in hours and days.
For example, in one review of cancer trials it took an average of 621 days to recruit the first patient after funding had been agreed. The recent H1N1 pandemic came and went in less time. “That might be okay for hypertension or diabetes in a developing country, but for a rapidly developing problem, we have to concertina that,” says Farrar. In ISARIC’s vision clinicians would develop these research protocols ahead of time and secure ethical and administrative approval.
When a crisis hits, these plans could be fed through a fast tracked system that allows research to start immediately. Farrar likens this system to the rapid response approaches already used by public health authorities.
“If there was an outbreak of salmonella in America tomorrow, there’ll be a really good, well-organised response from the CDC,” he says. “They won’t spend six months discussing a protocol and putting together a case record form. They go to a shelf and take off how they investigated it the last time.” Researchers also need to work from the same playbook, even if they hail from different regions or countries. If everyone records the same data then local information becomes globally useful.
“In an outbreak, you may only be able to study 20 patients in Vietnam, 30 patients in China, and 30 in Africa,” says Farrar. “We need to make sure that we standardise these things so that ultimately, we can bring all of that research together.” As the infections spread data would accumulate. To ISARIC’s researchers, it is crucial that such data be stored in a freely available repository. The open access movement has been very successful in promoting free access to the end results of research, such as data and publications.
But Farrar says that the same principles should apply to the materials that make research possible in the first place. “If you faced an outbreak of encephalitis in Outer Mongolia, you could go to an open access website and say, ‘This group in Vietnam have done lots of studies on encephalitis, and here are their case record form, inclusion criteria, and consent sheet.’ That might save you months of effort.” People also have to be ready for the chaos that epidemics sow.
“Things become significantly more difficult,” says Olliaro. “There’s disruption, panic, and a lot of media attention.”
Clinics are flooded with patients, and clinicians face extra burdens on top of their already busy schedules. They barely have time to do regular work, much less carry out additional research. As the epidemic continues clinicians could fall ill themselves, compounding any shortness of staff. If clinics are to cope they need specialists who are trained to carry out research in the event of an epidemic.
“You need an intervention squad,” says Olliaro. “They’re ready to go but don’t know when they’ll be called upon. In the mean time, they’re doing routine hospital work.”
Such systems would be impossible to create in the middle of a crisis: they need to be put in place in the breathing space between epidemics. For ISARIC, this does not mean just making plans and forms, but creating trust and connections between its international members. Hayden recalls that during the London meeting when the idea for a consortium was first mooted, “a lot of these groups didn’t even know what each other were doing.” Farrar says, “Ultimately, what drives science is still relationships.
The time to build trust is now, outside of the pandemic setting. Then, when you have a crisis, you can be on the phone to someone in Indonesia and they trust you because you’ve worked together and you didn’t steal their samples.” With their initial burst of funding, the ISARIC members have set up a secretariat and four working groups to advance their agenda.
The first working group is tasked with designing clinical trials that can begin now, but that can also adapt and continue in the event of an epidemic. The second group will collect and standardise the clinical data we already have on H1N1 and other emerging infections. The third will develop protocols for studying the basic biology of infections with epidemic potential, such as how they affect their hosts, what makes some people more susceptible than others, and how they might react to known drugs. The fourth group will map all the barriers to a rapid clinical response, and create an open access hub that is loaded with pre-approved plans and documents to be deployed in a crisis.
Within the next two years, ISARIC hopes to build up enough momentum to secure more funds for the research they devise and to sustain the collaboration in the years ahead. Their ambitions are large, but Steven Webb from the Royal Perth Hospital, Australia thinks that they need to move quickly. “There’s a window of opportunity for funding,” he says. “People tend to remember the last great threat to public health and, at the moment, attention has been drawn to infectious diseases because of the last pandemic. We look to capitalise on that window of opportunity before it closes.” Image by Eneas de Troya