Objectives Bench to bedside translation of groundbreaking treatments like chimeric antigen receptor T (CAR-T) cell therapy depends on patient participation in early phase trials. Unfortunately, many novel therapies fail to be adequately evaluated due to low recruitment rates, which slows patient access to emerging treatments. Using the Theoretical Domains Framework (TDF), we sought to identify potential patient barriers and enablers to participating in an early phase CAR-T cell therapy trial.
Design We used qualitative semistructured interviews to identify potential barriers and enablers to patients’ hypothetical participation in an early phase CAR-T cell therapy trial. We used the TDF and directed content analysis to identify relevant domains based on frequency, relevance and the presence of conflicting beliefs.
Participants Canadian adult patients diagnosed with haematological malignancies.
Results In total, we interviewed 13 participants (8 women, 5 men). Participants ranged in age from 18 to 73 (median=56) and had been living with haematological cancer from a few months to several years. We found participants were unfamiliar with CAR-T cell therapy but wished to know more about treatment safety, efficacy and trial logistics (domains: knowledge, beliefs about consequences). They were motivated by altruistic considerations, though many prioritised personal health benefits despite recognising the goals (ie, establishing safety) of early phase clinical trials (domains: goals, intentions). Every participant valued receiving medical advice from their haematologists and oncologists, though some preferred impartial medical experts to inform their decision making (domain: social influences). Finally, participants indicated that improving access to financial and social supports would improve their trial participation experience (domain: environmental context and resources).
Conclusion Using the TDF allowed us to identify factors that might undermine participation to a CAR-T cell therapy trial and to optimise recruitment processes by considering patient perspectives to taking part in early phase trials.
Trial regestration: NCT03765177; Pre-results.
- qualitative research
- clinical trials
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Strengths and limitations of this study
We sought to identify implementation barriers to trial participation in advance of a chimeric antigen receptor T (CAR-T) cell therapy trial to optimise recruitment strategies.
We used a comprehensive, evidence-based framework (Theoretical Domains Framework) to identify potential barriers and enablers to trial participation.
Patient voices were prioritised by ensuring patient views were sought out prior to trial launch and by involving patient partners in study design and analysis.
Study participants were self-selected and may not fully represent the diversity of haematological cancer patients who may be eligible for a CAR-T cell therapy trial.
Study results represent anticipated barriers and enablers based on participants’ consideration of hypothetically participating in a CAR-T cell therapy trial.
Chimeric antigen receptor T (CAR-T) cell therapy is a promising new treatment for people with relapsed or refractory B cell leukaemia and lymphoma.1 2 A systematic review of early phase trials assessing the safety and efficacy of CAR-T cell therapy found that 77% of patients with acute lymphocytic leukaemia and 54% of patients with other haematological malignancies that were treated with CD19 targeted CAR-T cells experienced a complete response.3 Efforts to refine production and improve toxicity management are ongoing but require further evaluation through rigorous early phase testing.4 Unfortunately, recruitment to adult cancer clinical trials remains a challenge, with participation rates ranging between 2% and 7%.5–7
Given the complex, resource-intensive and intricate nature of CAR-T cell therapy, recruitment strategies must be optimised to promote the timely evaluation of this novel therapy. Past research on patient barriers to participating in cancer clinical trials has underscored treatment arm preference, side effects, uncertain outcomes and the burden of participation, as key barriers to clinical trial participation while enablers have included expecting benefits, perceived low risk, altruistic considerations and hearing about trials from trusted physicians.6 8–12 Identified barriers and enablers that are specific to early phase cancer trials have included narrow eligibility criteria, design concerns, safety and toxicity issues, and patient refusals.13–15 Patient reasons for declining participation have included fear of side effects, expecting little benefit, declining health and being in good health.16 Motivations for participating in early phase trials include expecting health benefits, the absence of alternative treatment options and hearing about the trial from trusted healthcare providers.17–21
The role of physicians in encouraging trial participation has also been emphasised as an important factor as physicians may provide biased or unclear explanations of trial details.8 22–24 One study found that physicians who successfully recruited patients into trials were more likely to provide information regarding trial benefits, address patient concerns, explain side effects and offer resources to manage patient anxiety than those who were less successful at recruiting patients.23 Physicians have also identified barriers to screening for early phase clinical trials, including concerns over safety, narrowly defined inclusion criteria, and time and resource constraints (see Castillo et al. 2021. Hematologists’ barriers and enablers to screening and recruiting patients to a Chimeric Antigen Receptor (CAR) T cell therapy trial: A theory informed interview study; forthcoming). Though some work has begun to explore how to optimise strategies for improving trial recruitment by drawing on theory,25–27 most strategies for improving trial recruitment rates are seldom theoretically driven.25 Instead, many interventions focus on providing participants with information regarding clinical trials using various modalities (eg, video, website) and have had moderate or inconsistent effects on subsequent trial participation.28–31 This indicates a need for designing novel, fit-for-purpose strategies that go beyond information provision to ones that harness the cumulative evidence base associated with theory-informed approaches.32
The Theoretical Domains Framework (TDF) was developed to synthesise the key factors across theories of behaviour and behaviour change into 12 domains.33 The framework was then validated and expanded into 14 domains.34 The domains include factors known to affect decisions and actions and can be used to probe which barriers and enablers in which domains might be influencing a particular decision. The TDF is distinct from other approaches in that its breadth facilitates identification of particular anticipated barriers/enablers for a given trial and sets the stage for linking barriers and enablers to strategies that are consistent with behavioural change theory and tailored to a given trial’s anticipated barriers/enablers.33 35 We aimed to use this comprehensive framework to identify the breadth of anticipated and unanticipated (to the trial team) barriers and enablers to hypothetically participating in the first investigator-led Canadian CAR-T cell therapy trial for haematological malignancies. By using the TDF to identify anticipated barriers and enablers prior to trial launch, we aimed to inform strategies to support patients considering participation in the CAR-T cell therapy trial.
We used the TDF to guide qualitative study design, data collection and analysis.36 37 We conducted qualitative semistructured interviews to identify potential barriers and enablers to participation in an early phase CAR-T cell therapy clinical trial and used the Consolidated Criteria for Reporting Qualitative studies to guide the reporting of this study.38
Patient and public involvement in research
Patient partners provided guidance and feedback on interview guide development and the interpretation of results as described below.
Interview guide development
We defined our target behaviour according to the Action, Actor, Context, Target, Time framework that specifies target behaviours according to ‘who needs to do what differently,’ when, and in what context (see online supplemental file 1 for how the target behaviour was defined).39 We used the validated version of the TDF to develop interview questions and prompts to elicit views on factors that might impede or facilitate participation.33 34 Eligibility for the CAR-T trial was not assessed as part of this study. However, participants were asked to imagine they were eligible and to respond to hypothetical questions regarding potential barriers and enablers to trial participation. To ensure our questions were relevant and the phrasing was clear, we sought feedback from clinicians and piloted our interview guide with collaborating patient partners (TH and SS). The full interview guide is provided as online supplemental file 1.
The planned CAR-T trial is being offered to patients with refractory or relapsed acute lymphocytic leukaemia, chronic lymphocytic leukaemia and B cell non-Hodgkin’s lymphoma who have no other treatment options available. We opted to recruit adult patients who had been diagnosed with any type of haematological malignancy given that this patient population may be asked to participate in similar early phase immunotherapy cancer trials at some point in their illness trajectory and, therefore, serve as a useful analogue for identifying potential barriers and enablers to CAR-T therapy participation. Regardless, every effort was made to recruit patients who would likely be eligible for the proposed CAR-T trial. Prospective participants were referred to the study team by haematologists from two academic hospitals located in urban centres in Ontario and British Columbia (Canada). A national non-profit organisation also distributed emails through their local chapters so that members of the non-profit who expressed interest in participating in an interview could contact the research team. We followed the 10+3 rule to determine our target sample size and gauge whether we had collected enough data to delineate our conceptual themes while minimising participant burden.40
Interviews were transcribed verbatim and analysed using the qualitative data analysis software NVivo Pro V.11. Data instances (ie, interview excerpts) were deductively coded into domains by three members of the research team (SA, GC and MF) according to existing guidelines.33 34 37 SA and MF independently coded the first 10 interviews and GC and MF independently coded the last three interviews. Analysts met to discuss their coding strategies and resolve discrepancies. When analysts disagreed, they coded data instances into all domains for which an acceptable rationale was provided and noted what aspects of the data instance corresponded with identified domains. Double-coding was used to ensure our analyses did not exclude elements in the data due to a single analyst’s interpretation.
We then conducted a directed content analysis using the TDF as the guiding framework.37 41 Data instances within a given domain were inductively and deductively analysed for novel and expected domain specific content. A descriptive label or ‘belief statement’ was assigned to each data instance representing underlying beliefs, ideas and attitudes expressed by participants. Belief statements were then revised, compared and grouped into domain-specific subthemes based on similar qualities (eg, belief statements representing various concerns regarding treatment side effects). Belief statements and associated subthemes were further examined and grouped into broader within-domain categories where appropriate.
Counts were generated for data instances at the belief statement, subtheme and category level. Tables were generated showcasing categories, subthemes, belief statements, the number of participants that endorsed a specific belief and the frequency with which a belief appeared in the data set (see online supplemental file 2, for a comprehensive list of belief statements, subthemes, and frequency counts). We conducted a member check of our emerging analyses by providing a patient partner (TH) with a written summary of results (see online supplemental file 3).42 Feedback from TH informed our analysis of which beliefs were the most relevant to understanding participation in clinical trials. By considering the strength and relevance of beliefs, the presence of conflicting beliefs, and the frequency with which they occurred in the data set, we were able to identify key domains.37 Subthemes were compared across relevant domains to identify broad patterns in the data. Recurring themes and ideas that transcended key domains were synthesised into global themes representing the most important factors impacting the decision to participate in a CAR-T cell therapy trial.
Interviews were collected between October 2017 and June 2018. The first 10 interviews were conducted by SA, a woman-identified research coordinator with a master’s degree in health systems management, and the last three interviews were conducted by GC, a woman-identified research coordinator with a master’s degree in psychology. Both interviewers were trained in using the TDF and received guidance and feedback from an expert in TDF methodology and behaviour change theory (JP). SA and GC introduced themselves as research staff and stated the general goals of the research (to identify barriers and enablers to trial participation) as part of the consent process. Interviews were conducted over the phone (n=7) or in person (n=6). Caregivers were present during four interviews. Interviews were audio recorded and ranged in length from 23 to 63 min (median=40 min). Written consent was obtained from every participant.
Thirteen people living with different types of haematological cancers (eight men and five women) participated in interviews. None of the participants who contacted the research team refused to participate or dropped out of the study. Most participants (n=8) were recruited by their haematologists and five were identified by a non-profit organisation. Nine participants lived in Ontario and four lived in British Columbia. Participants ranged in age from 18 to 73 (median=56) and had been living with cancer from a few months to several years. Seven participants had a form of leukaemia. Two had acute lymphocytic leukaemia, one had chronic lymphocytic leukaemia and four had other diagnoses. Six participants had lymphoma with four specifying non-Hodgkin’s lymphoma and three specifying B cell lymphomas. Eight participants were undergoing treatment at the time of the interview and five were in remission. Every patient had received at least one round of chemotherapy, half had received three or more rounds of chemotherapy, and three participants had undergone a bone marrow transplant. Two participants had prior experience participating in a clinical trial but none had experience participating in immunotherapy trials or early phase cancer trials. All participants were interviewed during the design phase of the planned CAR-T cell therapy trial.
Data saturation occurs when no new themes emerge in the data. According to the 10+3 rule, saturation is achieved when no new shared themes appear in the last three interviews.40 We did not find new subthemes in the last three interviews for 13 out of the 14 domains. A new subtheme was identified in the Reinforcement domain in the thirteenth interview, however, given that the reinforcement domain was not identified as a key domain, this is not likely to diminish credibility of the results presented.
Key domains and global themes
Six domains were identified as relevant to understanding barriers and enablers to participating in an early phase CAR-T cell therapy trial: Beliefs about Consequences, Knowledge, Social Influence, Intentions, Goals, and Environmental Context and Resources. Key domain subthemes were organised into four global themes. Themes are briefly described below and are then discussed in detail.
The first global theme, Navigating Choice in the Face of Uncertainty (domains: knowledge, beliefs about consequences, goals) characterises the dilemma of high stakes decision making as it applies to participating in an early phase CAR-T cell therapy trial. These considerations were heavily influenced by the second theme, Trusting the Experts (domain: social influence), where patients described the importance of reviewing trial options with their physicians before making a decision to participate. The third global theme, Ambivalent Intentions (domain: intention), represents the difficulty in arriving at a firm position, or intent, on whether or not to participate. The last global theme, Enabling Resources (domains: environmental context and resources, social influence), describes the material and social resources that may influence participation and enhance patient experiences during the trial. Table 1 presents subthemes, example belief statements and representative quotes for each global theme and associated domains.
Global theme 1: navigating choice in the face of uncertainty
Participants demonstrated varied levels of knowledge about CAR-T cell therapy. Some (n=8) had heard about CAR-T cells from doctors, national organisations, and the news while others reported never having heard of them before the interview (n=5). Regardless, most expressed a desire to know more about treatment safety (n=11) and efficacy (n=10), including remission and survival rates as compared with other treatment options. Participants wished to know more about trial logistics (n=10) and agreed that receiving accessible trial information (n=7) online (n=4) and in written formats (n=6) that could be shared with family and caregivers was important to them (domain: knowledge).
The need for information was born out of concerns over side effects (n=7), including the risk of death (n=2) (domain: beliefs about consequences). Other participants were more concerned with reducing the experience of pain and discomfort (n=4) (domain: goals). One participant who had recently relapsed after receiving three rounds of chemotherapy indicated that they would prioritise quality of life over survival given their older age (domain: goals).
Despite these concerns, nine participants were motivated to participate in a clinical trial for the benefit of others though one participant indicated that altruism was not a motivating factor (domain: goals). Two explained their altruistic motivation as having ‘nothing to lose but lots to gain’. Most participants were also motivated by the prospect of achieving progression-free survival (n=10) or a cure (n=5) despite having been informed that the purpose of an early phase CAR-T trial would be to assess safety (domains: beliefs about consequences, goals). Given the high risks and rewards associated with CAR-T cell therapy, a young woman who had experienced complications during chemotherapy and had recently recovered from a bone marrow transplant likened early phase trial participation to a game of ‘Russian roulette’ (domain: Beliefs about Consequences), emphasising the complexity and severity of deciding to participate in an early phase trial given the uncertain outcomes:
R: … it’s this like thing that could potentially cure me and it could be really good for me but also I could die from it, you know, it’s freaky to think like oh this could cure me it’s like Russian roulette. It’s like this could be the bullet or this could not.
Global theme 2: trusting the experts
Every participant (n=13) wished to hear about a CAR-T cell therapy trial directly from their haematologist or oncologist and indicated they valued their specialist’s opinion (domain: social influences). When asked whose input they would want when considering participation, one participant responded:
R: My hematologist yeah. I mean they’re like the group of seven, they’re all a whole bunch of painters, you know, and they all sit together and discuss which I’m so fortunate. So yeah from the team from the haematology team that would be beneficial if it came from [them].
Family members (n=10), research staff (n=7) and other healthcare providers (eg, family physicians, nurses) (n=5) were also identified as influential persons. However, their input was secondary to the medical opinion of their specialist. Two participants indicated they trusted input from friends who were medical doctors the most (domain: social influences).
Global theme 3: ambivalent intentions
Most participants (n=11) wavered in their intentions suggesting they would participate if they knew they would benefit from doing so (n=9), if they had few other treatment options (n=6), if their participation would help others (n=4) and if their doctor asked them to participate (n=3) (domain: intention).
I’d say if I didn’t have any other decent options I guess like if I’m told after this next round whatever it is and it doesn’t work if I’m told, I’m sorry that’s really all we can do for you, I’d probably be very inclined to go into a study like that.
Two participants suggested that they would be more willing to participate in an efficacy trial than a safety trial (domain: intention).
Global theme 4: enabling resources
Participants agreed that having participation-related expenses paid for would alleviate the financial burden associated with attending frequent appointments. Participants indicated parking and transportation (n=11), medication (n=3) and childcare services (n=2) would be important resources to cover (domain: environmental context and resources). Caregiver costs (n=3) and accommodations (n=2) were important for those who anticipated having to travel long distances to participate in a trial (domain: environmental context and resources). One participant who routinely travelled several hours to receive treatment indicated that associated costs were a significant barrier and source of stress (domain: environmental context and resources). Conversely, some interviewees (n=6) indicated that they would not need any resources covered because they lived close to the hospital and did not mind paying for transportation (domain: environmental context and resources).
Some participants wished for greater access to social workers and psychological counselling (n=3) (domain: social influences). Others experienced difficulties accessing medical information and suggested a patient advocate would be helpful for presenting clinical trial options (n=5) and for accessing specialists who may be difficult to contact (domain: social influences):
When things are less than life and death, no our system is a little too backlogged. Various specialists are hard to get into unless you have somebody really fighting for you.
We sought to identify barriers and enablers to hypothetically participating in a planned CAR-T cell therapy trial and found that participants were often ambivalent in their views. Participants expressed wanting to know more about CAR-T cell therapy and the logistics of the upcoming trial. They expressed concerns about potential side effects and the impact of trial participation on their quality of life. Many stated they were motivated by the promise of improved health despite stating that they understood the trial would primarily test for safety. Participants indicated that receiving information from specialists was valued and that having expenses covered and accessing social support might address financial and social barriers and improve the quality of their experience during the trial. These factors contributed to ambivalent intentions regarding trial participation. Though participants indicated that having no other treatment options would increase their likelihood of participation, the barriers and enablers identified in this study suggest that other factors likely contribute to patient decision making.
Accessible knowledge about CAR-T cell therapy that could be shared with loved ones was identified as a potential enabler suggesting trial details should be offered to prospective patients and their caregivers in multiple and accessible formats (eg, printed, verbal, online) to facilitate decision-making. Though information-based strategies do not always improve trial comprehension43 or recruitment rates,30 providing simplified consent forms and greater opportunities for patient–researcher conversations may increase patient comprehension levels.44 Using decision aids may be one way to support patients in making autonomous, informed decisions rather than deferring to physician recommendations. Ongoing research suggests that decision aids may increase comprehension of trial information and reduce decisional conflict and decisional regret without biassing participant decisions about whether to participate,45–47 though more research is needed in this area.48 49
Participants in this study were motivated by the potential for health benefits and simultaneously expressed concerns over side effects. These findings resonate with Houghton et al’s conceptual model which indicates that prospective randomised controlled trial participants will consider what they stand to gain or lose, altruistic motives, social influences and the burden of participation.10 However, unique to the early phase cancer trial context is that patients often express therapeutic misconception (believing the intent of the trial is to benefit them)31 50 and unrealistic optimism (believing they will experience better outcomes than others),18 19 posing ethical challenges for trialists.51
Consistent with existing guidance on developing decision aids for clinical trials,48 it will, thus, be important to present CAR-T cell therapy safety and efficacy findings with an emphasis on how safety and efficacy data compare to usual care and other available options. Though the threat of adverse events remains, the likelihood of experiencing adverse side effects may be comparable to treatments they have already endured. Likewise, reiterating the probability of experiencing a health benefit using non-biased language may enable prospective trial participants to make an informed decision rather than remaining shrouded in uncertainty or expecting health benefits when they cannot be guaranteed. Up-to-date systematic reviews provide an ideal source for describing the state of the evidence and provide a basis for developing accessible materials for patients and caregivers.3 Patients can then be engaged in comparative imaginings of future outcomes to aid with their decision-making process.32
Role of haematologists and navigators
Physicians have a clear role in helping patients formulate a decision regarding trial participation. However, given the multiple demands on physicians’ time, patients could be directed to a patient navigator for trial information and social support. Patients who received support from patient navigators reported improved comprehension of clinical trials and a higher than average consent rate.52 53 Patient navigators may be a feasible strategy for meeting some patient needs during trial recruitment and participation. However, this warrants further research into the training necessary to ensure navigators do not inadvertently influence prospective trial participants (eg, by using personal narratives to convey information).54 55
Financial and social resources
Participants indicated that having expenses like parking and transportation, accommodation and childcare covered would enable their participation. This is notable as parking costs have been identified as a significant source of financial toxicity that may impact cancer care.56 Social and financial resources should be allocated according to individual need to ensure that those who require greater assistance are not excluded from trial participation due to financial or social barriers. It will be important to remain transparent about what support is available to ensure equitable access to resources given the funding constraints of the trial.
We used a comprehensive, evidence-based framework to ensure our findings on barriers and enablers cast a sufficiently wide net to capture likely impediments to participating in an early phase clinical trial. An advantage of the TDF is that key identified domains can be linked to evidence-based fit for purpose strategies to address barriers and enablers.32 Future research may seek to develop theory-driven strategies to better support patient decision making by mapping the barriers and enablers identified in this study to behaviour change techniques.57 Moreover, to the extent that other patient groups share similar barriers and enablers, similar strategies may serve to inform other similar trials.
We also prioritised patient voices by speaking with them in advance of the trial to ensure their perspectives were integrated in the trial design. Involving patient partners in this interview study helped to ensure our focus remained on patient identified priorities. Involving patient partners will continue as the trial progresses to ensure the research process remains relevant to patients. For example, patient partners have provided feedback on the trial protocol, consent forms, visual aides, and lay summaries, and in developing plans to organise a patient peer support panel.58
As the trial had not yet begun, the aim of the present study was to identify anticipated challenges to inform efforts to optimise early phase trial conduct once the trial was launched. One limitation of this study is that we captured hypothetical barriers and enablers to participating in a planned CAR-T cell therapy trial. There is an opportunity for future research to document experienced barriers and enablers to participating in CAR-T cell therapy trials during the trials to assess any additional experienced barriers/enablers and whether the trial recruitment activities sufficiently addressed anticipated barriers/enablers identified here.
Second, those who are most likely to participate in research often experience fewer logistical barriers, prefer interviews over other types of designs, are altruistically motivated, and value research.59 This may be why nearly half of interview participants indicated they did not need any resources to participate in a trial, which may not fully reflect the realities of prospective trial participants. Nevertheless, a number of barriers were identified in these participants, indicating that even a motivated subset of participants with few resource barriers may face challenges in participating that are worth addressing in the design and conduct of the trial. More work is needed to understand the experiences of patients who face multiple socioeconomic barriers.
Finally, though participants varied in age, treatment course and length of time living with cancer, there were no discernable patterns indicating that barriers and enablers differed across these dimensions. We also did not collect information on race and ethnicity. Future research should aim to understand how these factors may impact participant decision making and trial participation experiences.
Using qualitative methods guided by a comprehensive framework enabled us to identify barriers and enablers before the trial, affording us the opportunity to develop trial specific strategies based on trial-specific barriers and enablers to improve recruitment procedures. Using the TDF may prove useful to inform the development of other early phase trials by ensuring that any unexpected barriers can be addressed to improve participation rates to early phase clinical trials and ultimately accelerate access to promising lifesaving therapies.
We would like to thank the participants in this study, and their caregivers, who generously shared their time, experiences and wisdom with us.
Contributors GC conducted three interviews, analysed data and drafted the manuscript. ML and JP designed the study and provided guidance and oversight for the conduct of the study and reporting of this manuscript. JP provided methodological expertise and leadership. SA designed interview guides, conducted interviews and analysed data. MF double coded data, provided feedback on analyses, and facilitated patient partner involvement. NK, DAF, HA, RAH and RB provided medical expertise and guidance on study design and interpretation of the results. NK, HA and RB assisted in identifying prospective participants. KT provided socioeconomic expertise and guidance on study design. JM provided feedback on study conduct and interpretation of results. TH and SS provided feedback on study design and results from the patient perspective. All authors provided feedback on multiple drafts of this manuscript.
Funding The conduct of this study was supported by a Clinical Social and Economic Impact (CSEI) grant from Biotherapeutics for Cancer Treatment (BioCanRx) (Grant reference number: FY17/CSEI4). BioCanRx is funded by the Government of Canada’s Networks of Centres of Excellence. BioCanRx was not involved in any other aspect of the project, such as the design of the project’s protocol, methods, analysis plan, the collection of data and analyses. ML is supported by The Ottawa Hospital Anesthesia Alternate Funds Association and the Scholarship Protected Time ProgramProgramme, Department of Anesthesiology and Pain Medicine, Ottawa.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval This study received ethics approval from the Ottawa Health Science Network Research Ethics Board (approval #20170502–01H) and from the University of British Columbia - British Columbia Cancer Agency Research Ethics Board (approval #H17-01472).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as online supplemental information. The datasets generated and analysed during this study will not be made publicly available in order to protect the privacy and confidentiality of study participants. However, deidentified, aggregated data has been made available as online supplemental files.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.
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