Background

Earth is currently facing one of its most significant public health crises in modern history. Since the first cases of coronavirus disease (COVID-19) were notified in December 2019, the world has progressively struggled with this novel infection, seeking to understand its epidemiology, clinical significance, optimal patient management, and prevention and control strategies to reduce morbidity and mortality, as well as the socio-economic consequences.

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The initial research requirements in pandemics are predictable. Six weeks after Chinese health authorities announced the discovery of a novel coronavirus, the World Health Organization (WHO) established transmission dynamics, disease severity and immunity, and impact of control and mitigation measures as the main domains of research priorities to guide public health responses to COVID-19 [1]. Previous analysis of the scientific literature on severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS) identified ten major themes of research inquiry: clinical characterisation; prognosis; diagnosis; clinical management; viral pathogenesis; epidemiological characterisation; infection prevention and control/transmission among healthcare workers; susceptibility in the community; psychosocial impacts of disease and social isolation; and aetiology [2]. When the same research themes were applied to identify deficiencies in the understanding of COVID-19, it was clear that, although progress has been made, large knowledge gaps persist and no published data existed within some of the themes [2].

But how is it possible to study a disease that is so quickly spreading and to rapidly use that research to inform prevention, control, and treatment? In our view, a dilemma with such a wide-reaching impact mandates collaboration on a global scale. International research collaboration (IRC) is the best means to rapidly address these fundamental questions and potentially change the paradigm of data sharing, constrained by several ethical, legal, and social challenges in addition to technical (data quality, harmonization) and organizational hurdles, for the benefit of patients worldwide. Although several studies on IRC in the context of COVID-19 pandemic have been published, including calls to foster IRC, little is known about their effective impact. We therefore present an overview of IRC in COVID-19 including several examples and describing their scope and impact. We also discuss the benefits and challenges of IRCs in general and in the context of the pandemic, with particular attention to the situation in low and middle-income countries (LMICs).

In recent years, there has been increasing participation in IRCs in various forms, such as multicentre studies, international registries, evidence synthesis, and Delphi consensus studies for the creation of clinical practice guidelines [3]. These enable researchers to share their knowledge and combine perspectives to solve complex cross-disciplinary problems, creating higher impact outputs and contributing to overcome resource fragmentation. The critical mass to scale data generates power to promptly answer pressing clinical questions with generalizability, applicability, and scientific validity across multiple populations [4]. This value has been confirmed across diseases of all incidences and severities, and is possibly even greater in time-critical settings, such as pandemics [5].

Prior pandemics/epidemics, especially the influenza A H1N1 pandemic in 2009, together with major social and technological developments, resulted in the formation of several platforms to facilitate regional and global collaboration in infectious disease research (Table 1). Such consortia leverage scale, multi-disciplinarity, and data sharing to study a pandemic at its various stages in different countries and predict its course. These platforms help to answer critical clinical, public health, and socio-economic questions and provide important public goods.

Table 1 Examples of international research consortia launched in recent years in the context of infectious disease response
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Moreover, the use of shared research methodologies in diverse locations allows direct comparison between distinct populations, as well as over time. Shared databases encourage data completeness, quality control, harmonization, and facilitates data exchange. Finally, collaborative efforts ensure the synchronization of timelines and avoid competition among studies evaluating similar interventions.

COVID-19 has expanded across every LMIC, where the human impact may be greater. IRCs permit research to be conducted in countries that might otherwise lack the necessary resources and/or expertise. Collaborations of LMICs, so-called ‘South-South’ collaboration, such as the Africa Taskforce for Coronavirus (AFTCOR) or the aforementioned PANDORA, are often better placed to find solutions to their specific challenges and needs [17]. They also create a critical mass that facilitates cost-effectiveness, improves retention of talented researchers, and increases visibility and participation globally [17]. Many collaborative networks with LMICs also include high-income partners, referred to as ‘North-South’ collaboration [18]. These ‘North-South’ research collaborations previously demonstrated their utility to create global clinical guidelines taking into consideration the evidence base for interventions and the specific challenges of LMICs [3, 19]. In the case of COVID-19, this has facilitated the initiation and ongoing operations of studies within LMICs [8], including increased access to funding, resources, knowledge and experimental treatments with potentially widespread infectious disease control benefits that transcend geographical and socio-economic borders. Moreover, these IRCs also facilitate the investigation of the impacts of socio-cultural biases that might render policies like social distancing or generalised lockdowns untenable and ineffective and help to assess genetic factors that might influence a population’s susceptibility to the virus and treatment responses [18].

Perhaps the greatest advantages of IRCs for LMICs relate to the enhanced dissemination of findings fostering their global impact. In LMICs, traditional routes of scientific data dissemination have had a disproportionately low impact on healthcare practices, due to inadequate resources or decision-making to implement changes and to the reduced access of many healthcare practitioners to high-profile, English-language journals. IRCs involving multiple countries with different levels of affluence facilitate dissemination beyond traditional routes to include more local and open-access journals, newsletters from professional bodies, and media outlets.

Despite the many advantages of IRCs between high- and LMICs, various obstacles need to be overcome. Obstacles include the disproportionate influence of high-income countries on study agendas, which may skew benefits to their favour; ethical issues regarding inconsistency in the acquisition of patient consent, governance of health research, training of human resources, institutionalisation of scientific activity, access to research funds, and cultural aspects; lack of commitment to capacity building; and prioritization of limited resources to healthcare and other essential services in preference to research [20]. However, the mixed ‘patchwork’ of achievements and failures in COVID-19 response may suggest that higher-income nations are not maintaining their commitment to solidarity and equity [21]. Important measures of success of ‘North-South’ collaborations are not limited to scientific advances, but extend to the identification of priority areas of work, ensuring the sustainability of the interventions and investment in local research capacities [20]. The Global Effort on COVID-19 (GECO) Health Research, launched in May 2020 by the UK National Institute for Health Research, focuses on understanding the pandemic and mitigating its health impacts in LMIC contexts, encouraging project leadership from LMICs. Twenty projects have been funded until now tackling the consequences of COVID-19 in LMICs, focusing on topics such as transmission and infection control, long-term outcomes, and mental health issues [22, 23]. This and other initiatives attempt to balance discrepant access to research funds between high- and LMICs.

Another major obstacle includes the tremendous increase in the volume and complexity of administrative work and the logistics or contractual requirements for ethical data sharing, which may hinder research productivity. Deficiencies in open-data sharing mechanisms have been reported globally, which may be particularly relevant in LMICs [6, 24]. This highlights the urgent need for interoperable, open-data repositories including real-time deidentified data. Besides, issues with methodological aspects when reporting COVID-19 outcomes and risk factors contribute to increased variability across epidemiological studies [25].

Data sharing within a consortium faces barriers of different nature, as previously discussed. In IRCs, ethical and effective data-sharing can only be achieved by considering the interests of all relevant parties: research participants, researchers, and funders [26]. Researchers in LMICs have shown concerns regarding safeguards when handling data, including transfer to others, and possible lack of control over subsequent data use [27]. Efficient data-sharing frameworks and accountable governance, together with the establishment of institutional data access committees, are urgent requirements to ensure sustainable and fair international data sharing [27].

Data linkage infrastructure, allowing direct download of data from electronic medical records into research databases, changes the paradigm of collaborative medical informatics. Efforts toward the harmonization of data from different IRCs have been successfully implemented, for example in the case of COVID-19 dermatology registries [8, 28]. A recently proposed framework for a data-driven systems approach to the collection, management, and analysis of high-quality data to inform decision in managing clinical responses and social measures to overcome the COVID-19 pandemic and future health crises is currently under development [29].

There are also inter-personal issues, including the development of trust between investigators. The use of pre-existing networks where IRC is already established allows for that trust component to be integrated before a health crisis. IRC also requires funding, which is often subject to a variety of political influences, especially when it crosses borders. One solution to this issue is the creation of multilateral funding organizations, such as the Global Research Collaboration for Infectious Disease Preparedness (GloPID-R) that invests in research in new or re-emerging infectious diseases globally [30].

Despite such limitations, numerous international observational and randomised controlled trials are studying COVID-19. The COVID-19 pandemic has rapidly accelerated trends in international collaboration thanks to unique information sharing efforts and mobilization of resources [31, 32]. The pre-existing Short Period Incidence Study of Severe Acute Respiratory Infections (SPRINT-SARI) and the recently formed COVID-19 Critical Care Consortium (CCCC), each incorporating more than 350 hospitals in over 48 countries, have activated tiered data collection-based on-site resources, common case report forms, and global dissemination networks to provide observational data in critical care [8, 30, 33]. The Randomised, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) is a perpetual multinational trial that simultaneously evaluates interventions across multiple management domains, which can be adapted to evaluate treatment during respiratory pandemics [30]. Several consortia have been created to understand the risks associated with COVID-19 in patients with different comorbidities, such as the Surveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD) registry, the COVID-19 Global Rheumatology Alliance (COVID-19 GRA), the European Renal Association COVID-19 Database (ERACODA), the Global consortium study of Neurological Dysfunction in COVID-19 (GCS-NeuroCOVID) and the Thoracic Cancers International COVID-19 Collaboration (TERAVOLT) [25, 34,35,36,37,38]. Such consortia have also provided crucial data on other topics, ranging from the well-being of healthcare workers during the pandemic to weather and atmospheric factors contributing to COVID-19 transmission and fatality rates [39,40,41].

One of the best examples of multicentre research studies during the pandemic is the Solidarity Trial launched by the WHO. Interim results from the Solidarity Trial, enrolling almost 12,000 patients in more than 400 hospital sites in over 30 countries, revealed that all four treatments evaluated (remdesivir, hydroxychloroquine, lopinavir/ritonavir, and interferon) had little or no effect on overall mortality, initiation of ventilation, and duration of hospital stay in hospitalized COVID-19 patients [42]. Solidarity II, a global serologic study for COVID-19 launched by the WHO, will enable standardization of serologic assays worldwide and sharing of scientific protocols, training materials, scientific publications, and survey findings. The Coalition for Epidemic Preparedness Innovations (CEPI), together with the global Vaccine Alliance (Gavi) and the WHO, launched COVAX to ensure equitable access to COVID-19 vaccines.

As the pandemic has spread, the number of centres and investigators willing to work together has also increased, thus extending the reach of the consortium’s impact and the potential positive repercussions for the future. Conversely, new collaborative initiatives continue to emerge and calls for research cooperation with established platforms have been met with variable enthusiasm. By combining efforts, we can improve research efficiency and minimise the burden on participating centres. This work demonstrates the promptness and utility of IRCs during COVID-19, but also highlights several barriers that still need to be overcome to maximize their global benefit. Among them, issues regarding data sharing, quality control, and harmonization; ethical issues; and disparities between high income countries and LMICs emerge as the main obstacles for the success of IRCs during the COVID-19 pandemic.

Conclusions

Although the race for treatment and prevention continues, there is no doubt that research collaborations are driving COVID-19 knowledge and response. Facilitating IRC in infectious disease and building capacity in established collaborative platforms are imperative to efficiently answer the priority clinical research questions that can change the trajectory of a pandemic. Several obstacles still need to be overcome to maximize the global benefit of IRCs during the COVID-19 pandemic.