Talking to the people that really matter about their participation in pandemic clinical research: A qualitative study in four European countries

Abstract Background Pandemics of new and emerging infectious diseases are unpredictable, recurrent events that rapidly threaten global health and security. We aimed to identify public views regarding provision of information and consent to participate in primary and critical care clinical research during a future influenza‐like illness pandemic. Methods Descriptive‐interpretive qualitative study, using focus groups (n = 10) and semi‐structured interviews (n = 16), with 80 members of the public (>18 years) in Belgium, Spain, Poland and the UK. Local qualitative researchers followed a scenario‐based topic guide to collect data. Data were transcribed verbatim, translated into English and subject to framework analysis. Results Public understandings of pandemics were shaped by personal factors (illness during the previous H1N1 pandemic, experience of life‐threatening illness) and social factors (historical references, media, public health information). Informants appreciated safeguards provided by ethically robust research procedures, but current enrolment procedures were seen as a barrier. They proposed simplified enrolment processes for higher risk research and consent waiver for certain types of low‐risk research. Decision making about research participation was influenced by contextual, research and personal factors. Informants generally either carefully weighed up various approaches to research participation or responded instinctively. They supported the principle of using routinely collected, anonymized clinical biological samples for research without explicit consent, but regarded this as less acceptable if researchers were motivated primarily by commercial gain. Conclusions This bottom‐up approach to ascertaining public views on pandemic clinical research has identified support for more proportionate research protection procedures for publically funded, low‐risk studies.


| INTRODUCTION
Pandemics and epidemics of new and re-emerging infectious disease are unpredictable but recurrent events that threaten global health and socio-economic security. It is of utmost importance to human health that there is capacity to conduct time-critical, patient-centred research during a pandemic because such research offers the best strategy for mitigating impact on health and society. [1][2][3] Such research is necessary to help clinicians accurately diagnose and provide optimal treatment, to develop preventive interventions such as vaccines, and for policymakers to make decisions about strategies to prevent spread and mobilize health-care services. One of the major conclusions from the, fortuitously mild, 2009 H1N1 pandemic is that globally co-ordinated research capacity that can be rapidly mobilized is lacking.
Globally, the call has been made for pandemic planning to incorporate preparedness and capacity for conducting prospective patient-focused clinical research. 2,4 Such research should be relevant, methodologically rigorous and be held to the same standards of ethical conduct as research conducted in non-emergent times. 5 However, there are numerous barriers to conducting clinical studies during a public health emergency, not least of which is ensuring that participants have sufficient information and opportunity in which to make valid, informed decision about research participation. Routine research enrolment processes, which are both appropriate and important under usual circumstances, might be both disproportionate and counterproductive during a serious pandemic. The potential threat to human health that would occur with a serious pandemic is of such a magnitude that we must examine all barriers that prevent us conducting effective clinical research. An important but seldom examined consideration, when balancing the rights and protection of research participants against the public health impact of research, is the views and opinions of prospective research participants themselves.
The objective of this study was to ascertain the opinions of members of the public in four European countries regarding provision of information and consent to participate in research that should apply during a pandemic. Specifically, we sought to describe public understandings of pandemics and related research, to identify factors that influence people's decisions regarding research participation and to consider acceptability of alternate methods of enrolment to clinical research during a pandemic.

| Design and setting
This study was conducted as part of the European Commission funded Platform foR European Preparedness Against (Re-)emerging Epidemics consortium (PREPARE; www.prepare.eu). It aims to inform study optimization of multisite, pan European clinical studies in primary and critical care for over 5000 patients during interpandemic periods and in preparedness for a research response during a future pandemic. We used qualitative research methodology because we aimed to identify important issues from the perspectives of the public before attempting to quantify them. We therefore prioritized quality and richness of information gathering over quantity or prevalence of views. This work has informed construction of a survey instrument that is being applied to a large, representative sample.

| Recruitment and sampling
We selected one country each from northern, southern, eastern and western Europe, as defined by the United Nations macrogeographical regions. 6 Focus groups and interviews took place be-

| Data collection
Focus groups and semi-structured individual interviews were used.
Our rationale for using focus groups was to stimulate discussion between those involved, anticipating that this would give rise to varied ideas and perspectives beyond those of the research team. 7, 8 We held 10 two-hour focus groups. Topic guides were developed iteratively in two pilot focus groups (UK). Two focus groups were subsequently held in each of the four countries in accessible community venues.
Pilot data were included in the data corpus as there were no substantive changes to data collection procedures that invalidated their use.
We conducted 16 follow-up telephone interviews (15-30 minutes in length) within 2-7 days of focus groups with two informants from each group. We selected interviewees for these individual interviews who were less vocal in the group or those who had held discrepant or contrasting views. 7 Focus groups and interviews were conducted in the local language. A face-to-face training meeting of all focus group moderators was held prior to data collection to ensure consistency, cultural sensitivity and to inform reflexivity. All study materials were translated into local languages. Focus groups were conducted in the local language by two local researchers (one moderator and one observer). Local researchers came from a range of different backgrounds (sociology, primary care, public health, culture science). Post-group debriefing and the use of field notes further enhanced reflexivity.
Focus group questions were rooted in evidence on pandemic clinical research and standards for good clinical practice in research. 4,9,10 We used images and hypothetical scenarios of a moderate-risk influenza pandemic to stimulate discussion of participating in the following three research scenarios: a point of care test evaluation (primary care), evaluation of a routinely used antiviral medication with known safety profile (primary care) and evaluation of a newer antiviral medication with known safety profile (hospital intensive care unit) (Box 1). We also asked about the acceptability of conducting research that uses excess from routinely collected clinical samples, and enrolment to adaptive clinical trials (Box 1). We selected a moderate-risk pandemic influenza because an airborne virus, such as a novel influenza, is a likely candidate for an epidemic or pandemic spread that might affect European countries. Scenarios were aligned with clinical studies being conducted in PREPARE that aim to recruit patients from primary care and critical illness settings and that aim to generate evidence to inform clinical management of outbreak-related illness. We chose to avoid an outbreak with very high mortality, such as Ebola, which might polarize decisions and limit transferability of findings to a European context. We also asked about reasonable adjustments to research enrolment processes, that is from the point when a patient is identified as eligible to be invited into a study, through the process of information exchange to support their decision about participation, and, if selected, the provision of consent. Follow-up interviews aimed to capture post-group reflections.

| Analysis
Focus groups and interviews were audio-recorded, transcribed verbatim and translated into English. Local researchers checked each stage for accuracy. Data were analysed using the framework approach, which follows a systematic process moving from data management to description to interpretation. 11 We charted the focus group (NG) and interview (HS) data by identifying text that related to our study objectives as evidence of a particular theme. In this way, a visual overview of the data was produced from which patterns, including similarities and differences, could be identified. In practice, this involved charting data related to each specific objective on multiple Excel spreadsheets, which then formed the basis for team discussions regarding emergent, explanatory themes.
Charting the data enabled recognition of contradictory or opposing views. The process of charting gave rise to the initial coding frame, which was then sent to local researchers (MG, SA, MPV), who double coded one of their focus group transcripts, and gave feedback on the analytic frame. At this point, the analytic process moved further into an interpretative stage where links between themes and cases were explored to expand the explanatory frame. In this higher-level analysis, we aimed to identify the range and diversity of factors influencing decision making and retrospectively applied decision-making theory 12 in our analyses. NVivo 10 software (QSR International, Melbourne, Australia) was used to facilitate analysis.

| Rigour and quality criteria
We used the COREQ checklist when designing and reporting this study 13 and adhered to the following rigour criteria 14 : description of context, of informants and of the research process, methodological adequacy and reflexivity of the multidisciplinary research team.
Throughout the research process, we actively sought opportunities to consider how multiple perspectives influenced the research process.

| Ethical considerations
Researchers obtained local ethical approvals in each country.
Informants gave voluntary, written informed consent, and researchers guaranteed anonymity, confidentiality and data protection. Table 1 reports the characteristics of the 80 informants. Results were generally consistent across countries unless otherwise indicated in the text. In our follow-up interviews, no informants felt they had been misrepresented or had revised their opinions. Emotive descriptions included the unpredictability of an outbreak, the rapidity of spread, high mortality and difficulty with containment.  In Belgium, Spain and the UK, informants described desensitization to authorization processes as a consequence of being inundated with signing "terms and conditions" in daily life. As a result, authorization has become habitual and automatic and has lost meaning.

| Factors influencing decisions about research participation
Decisions about participation were influenced by a complex interplay between personal attributes, research factors and contextual cues.
Personal factors, such as age, life stage and previous ICU experience, were influential. For example, older informants felt their age made them more "philosophical" and described feeling more socially con- Perceptions regarding the benefit of antiviral medication in primary care (scenario 2) were mixed, but some respondents saw benefits to receiving this trial intervention if offered.

P6: f it shortens the period of infection for 1 week… then I would. (Spain)
In the ICU scenario (scenario 3), informants perceived that they would receive more effective treatment if in a trial than if not. Some informants said they would only participate if guaranteed to receive an experimental trial intervention. Fear, driven by a perception that that no known effective treatment may be available for a life-threatening illness meant that informants placed greater hope in the intervention's superiority. Informants were also motivated by altruism, social responsibility and by contributing to medical knowledge in the "long-term." They wanted to receive feedback about the outcome of research they supported and felt feedback of results was a neglected aspect of research participation, which reduced the chances of subsequent research involvement.
Benefits were weighed against perceived risks and burdens of research participation. For example, informants saw a hypothetical POCT requiring a nasal swab sample in primary health care (scenario 1) as minimally invasive and low risk and used phrases such as "its just a swab," "sounds harmless" and "no bother" as justifications for their decision to take part should they be invited. Risks of side-effects and scepticism that medication was necessary were reasons given not to take part in the primary care medication study (scenario 2).

P1: … I thought that with a viral infection you just have to let it run its course. …. So I'd have more objections in this case. I think: leave me alone; I'll let it run its course…. (Belgium)
In the ICU scenario (scenario 3), risks and burdens were judged proportionate to the context of critical illness in which the decision about research participation was being made. Informants expressed less concern about potential side-effects of new interventions, describing the critical illness scenario as being "serious" and "you're in dire straits" (Poland).
However, informants also described making a more instinctive, intuitive decision based on personal pre-disposition, rapid appraisal and perceptions of trust, particularly when feeling fearful or unwell.  However, a minority of respondents from all countries wanted upfront information about how and for what their sample might be used.

| Acceptability of using routinely collected clinical samples for research
They also sought assurance that their samples would not be used for commercial purposes and were generally less trusting of research funded by industry sponsors, or where financial gain was the main ultimate motive. A counter-argument was also raised, highlighting the need to support investment required to develop new, more effective products.

| Views on Participating in Adaptive Clinical Trials
Informants grasped the concept of the response-adaptive clinical trial design and viewed this as well suited to a pandemic context and liked the novelty, flexibility and potential for enhanced personal benefit. They took a pragmatic view about the potential disadvantage to being enrolled in a response-adaptive trial at an earlier stage, when less was known about which treatment was performing better.
P2: you're ill when you're ill aren't you?

P8: exactly (Wales)
A minority view held that the adaptability of the design implied that researchers were uncertain, "fiddling in the middle" (P4, UK 04) and that "perhaps traditional is safer, it can't go wrong" (P8, Spain10). On balance, informants felt that being given information about study design was less important than information about risk, burdens and benefits in informing their decision about taking part or not. If study design information was to be available upfront, informants said they would want to know about the potential for adaptation and how that might impact their involvement.

| DISCUSSION
We present a wide range and diversity of public views in four European countries about perceptions of research participation during a pandemic outbreak of a novel Influenza-like-illness. Informants supported the need for clinical research during a pandemic outbreak and endorsed simplified, proportionate research enrolment processes.
Informants valued regulatory oversight of clinical research but also described having become desensitized to consent and "disclaimer" rituals and would not want to be overburdened with decision making about participation in low-risk research when they were unwell. They viewed opt-out consent models for low-risk research as acceptable and, at times, preferable.
Continued public engagement about clinical research participation is essential, in particular, to clarify the distinction between clinical care and research participation and to mitigate therapeutic misconception. 15 In a pandemic outbreak, therapeutic misconception may be amplified as agreeing to be part of a trial might be seen as providing unique access to novel or better treatments, rather than access to treatments with, as yet, unknown effectiveness or superiority. 15 1,16 and may go some way to meet therapeutic expectations about trial participation in that these trial designs allow pre-specified changes to the chances of a participant being allocated to an intervention arm that starts to perform better, 17 thus participants joining a study later may be more likely to receive an effective intervention. 18,19 Some have raised concern that such studies can be complex to explain to patients, 20,21 and so could further complicate enrolment in a public health emergency. Our informants could grasp the responseadaptive trial design and saw it as advantageous, particularly during a pandemic outbreak, but did not necessarily consider information about study design as a priority during an outbreak. Our findings confirm the general public's acceptance of donating excess material from routinely collected clinical samples for biomedical research provided safeguards are in place to protect against identification of the individuals and that the research was being performed primarily for patent benefit rather than to make a profit. 22 Decisions about participation in research were influenced by a complex interplay between personal attributes, research factors and contextual cues. In some scenarios, informants deliberated, weighed the risks and benefits of taking part in the context of perceived illness severity and pandemic threat. Informants also described a more instinctive decision-making style. They described a pre-disposition to take part in clinical research or not, and then sought cues, particularly regarding trustworthiness, to confirm or contradict that position.
Others have made similar observations suggesting that rapid decision making at a time of increased risk and uncertainty may reflect a natural way that people have evolved to competently navigate complex environments. 23 These insights about the nuances of participant decision making challenge assumptions underpinning our current models of research enrolment and suggest they may be oversimplified.  actual experience. Despite training, there was some variation in the way informants were recruited and data were collected in different countries, which may have impacted our ability to compare across countries. The median age differences in different country data also limits our ability to compare directly across countries. Appropriate to the hypothesis generating nature of this work, we worked with a purposive sample which is designed to provide transferrable but not generalizable data. 25 We have used these findings to develop a cross-sectional survey of public opinion that will allow us to quantify views and consider generalizability in nationally representative samples in eight countries within the Organisation for Economic

| Strengths and weaknesses
Co-operation and Development (OECD).

| CONCLUSIONS
This work underpins the call to minimize regulatory burden for pandemic clinical research proportionate to the potential risk of harm.
Pandemic research requires flexibility, adaptability and co-ordination and sets an imperative for change in the current paradigm of research.
The public value safeguards of research regulation, but these should not present disproportionate, "one-size-fits-all" barriers to their participation. Opportunities for change may lie in new regulations guiding European clinical trials that now make provision for a new category of clinical study that poses minimal risk to participants. 26 Newly published ethical guidelines also offer advice regarding modifications to informed consent. 27 Effective pandemic preparation for clinical research requires active public involvement to mitigate therapeutic misconception, engender trust and promote innovation to the research process.
review of the manuscript). AK also transcribed data (Poland) and SA (Belgium), MPV (Spain) double-coded data. AW project administered the study, co-ordinated the focus groups in Wales and co-ordinated transcription and translation. KH, RM, PS contributed to study design.
AN contributed to study design, analysis and interpretation. He leads PREPARE-EARL and is principal investigator. All authors approved the final manuscript. and Antwerp University Ethics Committee, Antwerp, Belgium.

CONSENT FOR PUBLICATION
Not applicable.

AVAILABILITY OF DATA AND MATERIAL
The datasets generated and/or analysed during the current study are not publicly available due to protection of participant confidentiality but are available from the corresponding author on reasonable request.