Modernising epidemic science: enabling patient-centred research during epidemics

Strengthened global coordination and support for clinical research on EEIDs

It is worth considering the substantial difficulties that face those who wish to undertake clinical research on emerging and epidemic infections. First, many emerging pathogens might be considered rare. The European definition of a ‘rare disease’ is a disease that affects fewer than 1 in 2000 people, whereas the US definition is a disease that affects fewer than 200,000 citizens [29]. The diseases currently under the ‘rare diseases’ umbrella are largely severe non-communicable diseases with a genetic component, such as cystic fibrosis, or rare cancers. Although direct comparison of infectious epidemic diseases and rare non-infectious diseases is somewhat artificial, it can nevertheless be illustrative. SARS resulted in a total of 8096 cases [30]; 850 cases of avian influenza A/H5N1 have been reported since 2003 [31]; 684 cases of avian influenza A/H7N9 have been reported since March 2013; and 1733 MERS-CoV cases have been reported since September 2012 [32]. For comparison there are an estimated 14,000 people living with phenylketonuria and around 225 new diagnoses of Ewing sarcoma annually in the US alone. Second, the timeframe for action can be both unpredictable and extremely short, with the average duration of influenza epidemics being 10 weeks, with the peak incidence reached after only 4 weeks [33]. Third, the spatial distribution can be widespread. The 660 patients diagnosed with avian influenza A/H7N9 in China between March 2013 and September 2015 were admitted to 258 different hospitals, an average of under one patient per hospital per year (personal communication, Yu Hongjie, China CDC). The 854 H5N1 cases reported since 2004 have arisen in 16 different countries [34].

The bottom line is that the unpredictability, rapidity and rarity of many emerging infectious disease outbreaks render it improbable that a meaningful research response can be delivered by isolated investigators or institutions. Large-scale international collaboration is essential. In the wake of the West Africa Ebola outbreak, several initiatives have highlighted and attempt to address key deficiencies in our ability to respond to major infectious disease outbreaks. These include the newly established WHO Health Emergencies Programme, the WHO RD Blueprint for Action to Prevent Epidemics, the report of the Commission on a Global Health Risk Framework for the Future, and the Coalition for Epidemic Preparedness Innovations. However, none of these initiatives specifically or adequately address the weaknesses of platforms for conducting essential clinical research both before and during outbreaks. This renewed interest in global health security and in research and development for epidemic infections is to be welcomed but must be accompanied by investment in a sustainable operating model for EEID clinical research networks. Otherwise the clinical research platforms and tools that are needed to rapidly characterise emerging infectious threats and to evaluate the products of diagnostic, drug and vaccine development pipelines will, once again, not be there when we need them.

One of the earliest clinical research networks with a specific focus on EEIDs was the South-East Asia Infectious Diseases Clinical Research Network (SEAICRN), which was established in response to the re-emergence of avian influenza A/H5N1 in 2003. Following from SEAICRN, the International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) was established in 2012 as a global investigator-led network-of-networks aiming to ‘foster global collaborative patient-oriented research between and during epidemics’ [35]. ISARIC members have subsequently been prominent in the development of two further regional clinical research networks focused on preparedness for emerging and epidemic infections: the European Commission-funded Platform for European Preparedness Against (Re-) emerging Epidemics (PREPARE) and the Australian Partnership for Preparedness Research on Infectious Disease Emergencies (APPRISE). These networks have made significant contributions to building capacity [36], linking researchers, developing tools such as syndrome-based clinical characterisation and generic treatment trial protocols [35, 37, 38], identifying ethical and legal barriers [39], and responding to outbreaks [40–48].

However, sustaining and coordinating EEID clinical research networks is a major challenge when both disease incidence and funding are unpredictable and fluctuating. It simply is not realistic to establish and maintain epidemic clinical research capabilities in every centre where an outbreak might occur. This is particularly true in areas where poverty and inadequate healthcare systems mean that despite increased vulnerability to epidemic infections there are far more pressing day-to-day priorities. This does not mean that the only answer is to parachute researchers into an affected area. A model that has worked well for rare non-communicable diseases is the establishment of Rare Diseases Clinical Research Consortia, which are supported by a Rare Diseases Data Management and Coordination Center. This may be a good model for EEIDs, where geographic or disease-specific clinical research networks working on day-to-day infectious diseases problems (including drug-resistant infections) are primed and incentivised to respond to outbreak infections, and are supported by a centre of excellence that houses the expertise and resources required to develop and test new methods and tools, to coordinate or lead multi-centre research on EEIDs, and to provide much needed support and tools to local investigators in the event of an emergency. This might be conceptualised as a multiple hub-and-spoke, or dandelion, model, where each research network has its own hub, but each hub can call on the support and resources of a central centre of excellence.