Are there opportunities for a closer collaboration on clinical stroke research in Europe?

Abstract

Introduction

One of the aims of the European Stroke Organisation (ESO) is to facilitate academic, multinational clinical stroke research. However, despite examples of successful regional and national stroke research networks and collaborative groups, there is no organisational structure at a European level that can facilitate multinational clinical stroke research.

Materials and methods

In a project including a survey and a workshop and involving stroke researchers in the ESO, we sought to identify the challenges faced by existing clinical stroke research networks, to define the purpose and roles of any future European stroke research collaboration, and to propose an organisational structure.

Results

The survey and workshop gave strong support for an alliance model with independent network members, with the purpose of facilitating clinical stroke research through improved coordination and communication, provision of support, education, and advocacy and communication with other stakeholders. The focus of a proposed European clinical stroke research alliance should be multinational randomised-controlled trials in acute care, prevention and rehabilitation, but the alliance could also support other forms of multi-national clinical stroke research.

Conclusion

There is an interest for increased collaboration on multinational clinical stroke research in Europe, in the form of an alliance of independent research networks and collaborative groups. The ESO Trials Network Committee will continue consultation with existing stroke research networks and collaborative groups, and other key stakeholders, to assess the feasibility and support for development of an ESO Trials Alliance.

Introduction

Stroke is a significant cause of health loss and economic costs in Europe, and the burden of stroke varies substantially between different countries.^1,2 Research into prevention, acute treatment, rehabilitation and service delivery is essential to improve stroke care and to reduce inequities in stroke services throughout Europe. Although industry-led clinical trials are an important contributor, many key advances in clinical stroke research have resulted from academic, investigator-led trials. ³ However, large multinational trials are becoming increasingly difficult to do, due to the recognition of the need for large sample sizes, increasing regulatory demands, differences in regulatory demands in different countries, and increasing costs. ⁴ In some countries, stroke research networks have been shown to facilitate the conduct of randomised-controlled trials and to increase efficiency of research (Gary Ford, personal communication), but on a European level there is no organisational structure to facilitate large multinational clinical stroke studies. In a project including a survey and a workshop and involving stroke researchers in the European Stroke Organisation (ESO), we sought to identify the challenges faced by existing clinical stroke research networks and other collaborative groups in Europe, to assess whether there is a scope for closer cooperation between networks, to define the purpose and roles of any future European clinical stroke research collaboration, and to propose an organisational structure (Panel 1). This report summarises the survey and workshop conclusions.

Panel 1. Aims of this project
• To identify the challenges faced by existing clinical stroke research networks in Europe
• To assess if there is scope for a closer European collaboration on clinical stroke research
• To define the purpose and role of a collaboration
• To suggest an organisational structure for a collaboration

Methods

The project used a mixed methods approach, including a survey among European stroke trialists and a workshop among participants at the ESO Conference in Prague in 2017. Participants were informed of the plan to publish the results. As the project used responses from professionals and information from current practice, no formal ethical approval or written consent was deemed necessary.

Survey

We contacted all national stroke organisations registered in ESO and invited each organisation to send two representatives to a workshop about closer collaboration on clinical stroke research in Europe. We also sent invitations to individual members of ESO. People who registered for the workshop were asked to participate in a web survey. The questions were organised in three themes: (1) types of existing clinical stroke research networks, and challenges faced by these networks; (2) possible purpose and role of a European clinical stroke research collaboration; and (3) possible organisational structure of a European collaboration. For the purpose of this analysis, we only used the responses from survey participants from European countries.

Workshop

The first three themes in the survey were translated into three broad questions for discussion in groups: (1) What are the challenges for clinical stroke research in Europe?; (2) What could be the purpose of a European clinical stroke research collaboration?; and (3) What could be the structure of such a collaboration? In addition, we added a fourth question: (4) What could be the next steps and goals? Participants were divided into four groups of around 30 participants, by alphabetical order of participants’ names, and each group discussed two of the four questions. Conclusions from all eight group discussions were presented and discussed in a plenary session. The eight group discussions and the plenary session were chaired by members of the ESO Trials Network Committee.

Results

In total, 120 people from 37 countries attended the workshop, including 95 people from 27 European countries. Eight European countries were represented by delegates from national stroke organisations. Of the 120 participants, 94 had completed the survey, of whom 80 were from European countries and contributed to the results reported here. Participants in the survey were allowed to give more than one answer to each question, so the number of responses may sum up to more than the number of participants.

Existing networks and their challenges

Responses to the survey showed that 40 of the 80 European respondents (50%) were from countries with no network or collaborative group performing multicentre clinical stroke trials. The remaining 40 respondents reported varying levels of multicentre collaboration. Twenty-four (30%) respondents were from countries with a collaborative research group, while 13 (16%) and 12 (15%) respondents were from countries with a structured regional or national clinical stroke research network with core funding for a management team (Table 1). The biggest challenges for respondents were obtaining funding (23 of 80 respondents, 29%), followed by regulatory barriers (9 respondents, 11%), lack of central management teams (9 respondents, 11%), and insufficient protected time to conduct research for local investigators (9 respondents, 11%). Other challenges are shown in Table 1.

Table 1.

Types of clinical stroke research networks and collaborative groups in Europe, types of challenges, and funding opportunities, as reported in the survey.

	n (%) (n = 80)
Types of network
No network	40/80 (50)
Informal group of centres working together on  trials	24 (30)
Regional network	13 (16)
National network	12 (15)
Challenges faced by networks and collaborative groups
Insufficient funding	23 (29)
Strict regulatory demands	9 (11)
Lack of central coordination	9 (11)
Insufficient protected time for local investigators	9 (11)
Insufficient research infrastructure at local  centre	5 (6)
Lack of staff at local centre	5 (6)
Insufficient staff expertise at local centre	4 (5)
Unavailability of contact information about  potential local investigators	4 (5)
Insufficient research unit expertise at local  centre	3 (4)
Many competing trials	3 (4)
Few trials of interest	2 (3)
Strict requirements for data management at  local centre	2 (3)
Funding opportunities
Funding for national trials	58 (73)
Funding for multinational trials	40 (50)
Funding for national arm of multinational trials	20 (25)

Participants in the survey were allowed to give more than one answer to each question, so the number of responses may sum up to more than the number of participants.

Obtaining funding was identified as the commonest challenge faced by the survey participants. Most participants (58 of 80, 73%) reported that they had been successful in securing funding for national trials (Table 1). However, only 40 of 80 respondents (50%) had received grant funding for multinational trials led from their own country, and only 20 (25%) had been successful in obtaining funding for national participation in multinational trials led from another country.

The survey and the workshop also gave examples of successful regional or national clinical stroke research networks in Europe (Panel 2).

Panel 2. Examples of successful regional or national clinical stroke research networks in Europe
1. National Institute for Health Research (NIHR) Stroke Research Network (UK). The NIHR Stroke Research Network 5 was established in 2005 with funding for a national coordinating centre of directors and managers, and eight regional networks, each with a clinical lead and network manager. Regional networks employed research nurses and coordinators within stroke services to support recruitment of patients into multicentre stroke trials. The network also supported development of research proposals, and involvement of stroke patients and carers in supporting stroke trial delivery. Recruitment of UK stroke patients into randomised-controlled trials and other studies increased over five-fold from 2200 to over 12,000 patients per annum, with over 95% of UK acute stroke services recruiting stroke patients into trials. In 2013 the network was incorporated into the NIHR Clinical Research Network which provides support to recruitment of patients into clinical research studies of all specialties.
2. COllaboration for New TReatments of Acute STroke (CONTRAST) consortium (The Netherlands). The CONTRAST consortium 6 was formed in 2017 by eight university hospitals in collaboration with other large stroke centres. It has a scientific committee with representation from the university hospitals. The consortium also has a central management team, and offers limited financial support to local staff (e.g. doctoral students and research nurses). Funding is provided for the next five years by the Dutch Heart Foundation and the Dutch Brain Foundation. Several private parties also contribute substantially, without influence on study protocols or conduct or reporting of studies.
3. Catalan Stroke Code and Reperfusion (Cat-CSR) Consortium (Catalonia, Spain). The Cat-CSR consortiium 7 is a regional network which is a part of the Catalan Stroke Programme, funded by the Catalan Health Department since 2006. The consortium comprises a network of comprehensive stroke centres, primary stroke centres and “telestroke” centres, and has a scientific committee with representatives from all comprehensive stroke centres. The consortium has a central management team, and offers research infrastructure support to local centres.

Purpose and roles of a European clinical stroke research collaboration

The workshop participants gave strong support to the suggestion that there is a need for a closer collaboration on clinical stroke research in Europe. There was also a strong endorsement for the idea that the purpose of a European collaboration should be to facilitate clinical stroke research between existing regional or national networks or other collaborative groups, rather than starting or managing its own research. In the survey, all 80 respondents agreed that the collaboration should focus on randomised-controlled clinical trials, and that the focus should be equally on trials of acute stroke treatment, prevention, and rehabilitation (Table 2). There was also support from 51 of the 80 respondents (64%) for the proposal that the collaboration should include other types of clinical research, such as observational studies.

Table 2.

Purpose and roles of a European clinical stroke research collaboration, as reported in the survey.

	n (%) (n = 80)
Purpose
Facilitation of clinical trials of new (or new uses of existing) treatments	80 (100)
Treatment of acute stroke	80 (100)
Prevention of stroke	79 (99)
Rehabilitation after stroke	78 (98)
Facilitation of other types of clinical stroke research	51 (64)
Facilitation of clinical trials in other areas of medicine	26 (33)
Coordination and internal communication
Coordination between European investigators conducting trials	79 (99)
Regular reporting to members	77 (96)
Identification of local investigators to participate in trials	70 (88)
Provision of resources
Development of a registry of investigators and centres	70 (88)
Identification of funding opportunities	79 (99)
Education and training
Conduct of clinical trials	71 (89)
Conduct of other types of clinical research, and methodology	64 (80)
Communication with other stakeholders
Communication with policy-makers, research funders and the general public	74 (93)
Interaction with industry (drug, device, or diagnostics industries)	64 (80)
Linkages with patient organisations	56 (70)

Participants in the survey were allowed to give more than one answer to each question, so the number of responses may sum up to more than the number of participants.

Table 2 also indicates the possible roles of a European clinical stroke research collaboration, as identified by the survey. Coordination of research and communication between members were seen as the main roles of a collaboration, including coordination between European researchers conducting trials (79 of 80 respondents, 99%), regular reporting to members (77 respondents, 96%), and identification of investigators interested in participating in clinical trials (70 of 80 respondents, 88%). Most participants also agreed that the collaboration should provide resources to facilitate the conduct of multinational trials, such as registries of investigators and centres (70 of 80 respondents, 88%), as well as overviews of funding opportunities at national and European levels (79 respondents, 99%). Education and training were also seen as important tasks, including training in the conduct of clinical trials (71 of 80 respondents, 89%) and in research methodology, e.g. epidemiology (64 respondents, 80%). Finally, the majority of participants recommended that the collaboration should play a role in advocacy and communication with other stakeholders, such as policy-makers, research funders and the general public (74 of 80 respondents, 93%), industry (64 respondents, 80%) and patients’ representative groups (56 respondents, 70%).

In addition to the roles identified in the survey, the workshop participants also discussed whether a European clinical stroke research collaboration should be involved in research prioritisation. Although many participants saw the need for research prioritisation, most participants felt that members of the collaboration should be independent and free to decide which research questions to prioritise and which trials to support. Panel 3 gives examples of possible roles of a European clinical stroke research collaboration, as identified in the survey and the workshop.

Panel 3. Possible purpose and roles of a European clinical stroke research collaboration
• Coordination and internal communication
• Provision of resources
• Education and training
• Advocacy and communication with other stakeholders
• Linkage with other stroke research networks outside Europe

Structure of a European clinical stroke research collaboration

Consistent with the majority view that the purpose of the collaboration should be to foster research started and managed by its members, participants at the workshop gave strong support to the idea that a multinational collaboration should build on the “alliance” model, guided by three main principles (Table 3): (1) non-hierarchical structure, with wide consultation among members, to maximise member ownership and participation (77 of 80 respondents, 96%); (2) realistic goals for development of a collaboration, in a gradual and stepwise manner (72 respondents, 90%); and (3) independence of existing networks and collaborative groups, with freedom to decide level of involvement and activities to support (76 respondents, 95%).

Table 3.

Structure of a European clinical stroke research collaboration, as reported in the survey.

	n (%) (n = 80)
Non-hierarchical structure (wide consultation and guidance by members)	77 (96)
Realistic goals and gradual and stepwise development	72 (90)
Independence of existing networks and collaborative groups	76 (95)

Participants also discussed alternative, more structured network models ⁸ that have been used in regional or national networks. In a “gateway network” model, a representative committee will select trials for adoption by the entire network, after considering funding and competing research projects. Funding and management will be provided by the individual trial coordinating centres, whereas the network will provide varying degrees of general support (e.g. trial nurse, pharmacy support). Examples of such networks are the NIHR Clinical Research Network in the UK, ⁵ Australasian Stroke Trials Network, ⁹ and the Canadian Stroke Consortium. ¹⁰ A “fully managed network” model combines the gateway committee to select trials with full support for trial management (e.g. data management, monitoring). In this model, the trial coordinating investigator typically provides scientific leadership, working closely with the trial management team. An example is StrokeNet in the USA, funded by National Institutes of Neurological Disorders and Stroke. ¹¹ There are also other solutions, with elements from both models, such as the CONTRAST consortium in The Netherlands. ⁶ However, the workshop participants saw many challenges with implementing any of these models on a multinational, European level: First, unlike regional or national networks, a multinational network would have to deal with differences in structures, practices and regulations across countries, and a large central trial team would be needed to manage multiple trials in multiple countries. Second, funding would be a challenge, as there is no sustainable core funding to support a central office to manage trials across several European countries. For example, the EU Horizon2020 grants are limited to five years, and are suited for specific projects, but are not well suited for sustained funding of research infrastructure. Third, a “gateway” or “fully managed” network model, with a central committee to select trials to be conducted across the network, may be perceived as a threat to the independence of regional or national networks. Panel 4 shows the guiding principles in the “alliance” model.

Panel 4. Guiding principles for a European alliance of clinical stroke research networks
• Non-hierarchical structure, with wide consultation among members
• Realistic goals and a gradual and stepwise development
• Independence of existing networks and other collaborative groups

The next steps: development of a European alliance of clinical stroke research networks

The workshop participants finally discussed the next steps. There was strong support for the ESO Trials Network Committee to develop this project, through consultation with ESO governing bodies and members, existing clinical stroke research networks and collaborative groups, national stroke organisations, research funders and other key stakeholders.

Discussion

In this project involving stroke researchers from 27 European countries, we found that existing clinical stroke research networks face many of the same challenges, and that there is an interest in a closer collaboration, in the form of a European alliance of independent networks and collaborative groups. The participants suggested that the alliance should have a non-hierarchical structure, realistic goals and a gradual and stepwise development, and promote independence of member networks and groups. They also suggested that it should focus on facilitating the conduct of randomised-controlled trials, but could also be inclusive of other types of clinical stroke research.

An alliance model for collaboration has been successful in other areas of clinical research. The International Forum of Acute Care Trialists (InFACT) ¹² is a global alliance of regional and national networks for critical care research, funded by small grants from national organisations. It has a small executive committee and a council of members’ representatives, and is not involved in trial management, but operates by fostering research collaboration. There is no “gateway” committee, and trials are not formally approved, but discussed at meetings, and member networks can participate if they are interested. Working groups are formed by researchers with shared interests to address funding and conduct of specific projects. A similar approach is also being adopted by the Global Alliance of Independent Networks focussed on Stroke (GAINS), ¹³ which is a recent initiative to stimulate international collaboration in clinical stroke research across the world.

This project gathered stroke researchers from the majority of European countries, and used a systematic approach to identify existing challenges and to define the purpose, roles and structure of a possible European stroke research collaboration. However, we acknowledge weaknesses such as the limited number of participants, the limited number of delegates from national stroke organisations, the possibility of bias caused by selective participation and our subjective interpretation of the conclusions at the workshop, and the lack of involvement of other key stakeholders, such as patient organisation representatives and research funders.

In conclusion, we have found that there is an interest for increased collaboration on multinational clinical stroke research in Europe, in the form of an alliance of independent research networks and collaborative groups. Such an alliance could learn from existing alliances in other areas of clinical research and integrate with stroke research networks in other parts of the world, and can potentially lead to more, bigger, and better European clinical stroke studies. The ESO Trials Network Committee will continue consultation with existing stroke research networks, collaborative groups, and other key stakeholders, to assess the feasibility and support for further development of an ESO Trials Alliance.