Objectives Early phase cell therapy trials face many barriers to successful, timely completion. To optimise the conduct of a planned clinical trial of mesenchymal stem cell (MSC) therapy for chronic stroke, we sought patient and physician views on possible barriers and enablers that may influence their participation.
Design Semistructured interview study.
Setting Patients were recruited from three rehabilitation centres in Ontario, Canada; physicians were recruited from across Canada through snowball sampling.
Participants Thirteen chronic stroke patients (patients who had experienced a stroke at least 3 months prior; 10 male, 3 female) and 15 physicians (stroke physiatrists; 9 male, 6 female) participated in our interview study. Data adequacy was reached after 13 patient interviews and 13 physician interviews.
Methods Interview guides and directed content analysis were based on the Theoretical Domains Framework (TDF). Interviews were coded, and relevant themes were identified.
Results Most patients were optimistic about participating in an MSC therapy clinical trial, and many expressed interest in participating, even if it was a randomised controlled trial with the possibility of being allocated to a placebo group. However, the method of administration of cells (intravascular preferred to intracerebral) and goal of the trial (efficacy preferred to safety) may influence their intention to participate. All physicians expressed interest in screening for the trial, though many stated they were less motivated to contribute to a safety trial. Physicians also identified several time-related barriers and the need for resources to ensure feasibility.
Conclusions This novel application of the TDF helped identify key potential barriers and enablers prior to conducting a clinical trial of MSC therapy for stroke. This will be used to refine the design and conduct of our trial. A similar approach may be adopted by other investigators considering early phase cell therapy trials.
- mesenchymal stem cells (MSCs)
- stem cells
- cellular therapy
- chronic stroke
- theoretical domains framework
- clinical trials
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- mesenchymal stem cells (MSCs)
- stem cells
- cellular therapy
- chronic stroke
- theoretical domains framework
- clinical trials
Strengths and limitations of this study
Our study addresses an important gap in the literature: assessing barriers and enablers to participation in early phase trials.
Our interview guides and analyses were informed by the Theoretical Domains Framework.
The individuals who participated in our interview study may generally be more open to participating in research and thus have different views from those who declined to participate.
This interview study provides a needed comprehensive analysis of a novel topic.
Patient recoveries following stroke tend to plateau in the chronic phase resulting in continued deficits.1 A number of preclinical studies suggest mesenchymal stem cells (MSCs) may be effective in the treatment of ischaemic stroke2 given their anti-inflammatory properties,3 4 ability to generate trophic factors2 and potential regenerative capacity.5 Recent systematic reviews of MSC therapy for stroke suggest that the treatment appears safe; however, larger, more rigorously designed trials are needed to assess its safety and efficacy.6
When planning clinical trials, ensuring feasibility is of great importance; many trials do not meet intended recruitment objectives by anticipated deadlines (86%) or at all (19%).7 8 This suggests that engagement of patients and physicians in clinical trials needs to be improved. Systematic reviews have identified multiple barriers to trials including treatment preferences, issues with consent and information, fear of potentially endangering physician–patient relationships and a shortage of resources.9 10 However, available studies on these issues are retrospective, have methodological limitations and focus on later phase trials. Within the field of early phase cell therapy trials, there is a paucity of data on the barriers and enablers to patient and physician participation in clinical trials. A recent narrative review discussing a group’s experience in recruitment for cell therapy for stroke trials identified several potential patient barriers, including misconceptions regarding stem cells and a preference for single arm designs11; however, a formal assessment of barriers was not performed.
In preparation for a new clinical study of MSC therapy for chronic stroke, we sought to prospectively identify potential barriers and enablers using the Theoretical Domains Framework (TDF). The TDF is an established framework that synthesises theories of behaviour change into a parsimonious set of domains that represent influences on decisions and actions: knowledge, skills, social/professional role and identity, beliefs about capabilities, optimism, beliefs about consequences, reinforcement, intentions, goals, memory, attention and decision processes, environmental context and resources, social influences, emotion and behavioural regulation.12 The TDF is commonly applied to identify barriers and enablers to healthcare provider behaviour change using interviews or surveys.13 The TDF has been used to prospectively identify potential barriers and enablers to clinical trial participation, such as physician involvement and parent participation in a stem cell therapy trial for neonatal bronchopulmonary dysplasia to inform an early-phase clinical trial14 and healthcare provider ordering and setting of individualised dialysis temperature to inform a large-scale pragmatic cluster randomised trial.15 Here, using a comprehensive, qualitative interview approach, we applied the TDF to investigate barriers and enablers that would influence patient and physician participation in a clinical trial of MSC therapy for chronic stroke.
Written and/or verbal informed consent was obtained from all participants, and all procedures followed were in accordance with institutional guidelines.
Patient and public involvement
Patient input was obtained on the development of the interview guide. Two patients provided feedback on the interview guide. Refinements based on this feedback were made by the research assistant.
Interview topic guide
The TDF (version 2)12 16 was used to develop semistructured interview guides for both populations. The TDF synthesises key psychology and behaviour change theories and associated constructs into 14 theoretical domains that can be applied to understand barriers and enablers to behaviour change.12 16 For this study, behaviours of interest were defined using the Action, Actor, Context, Target, Time (AACTT) framework to ensure study of specific behaviours (table 1).17–19 Details of the interview guide can be found in online supplementary methods I-III.
Stroke survivors who had suffered a stroke at least 3 months prior were identified by physiatrists at their discharge from stroke rehabilitation at one of three centres: a rehabilitation centre within a tertiary care centre, an inpatient rehabilitation centre and an inpatient and outpatient rehabilitation centre within a regional care centre. Patients were provided with an information sheet explaining the study rationale. This description stated that laboratory studies suggest MSCs may be beneficial for stroke survivors and that we were interested in understanding patients’ current beliefs and knowledge to help improve a planned trial. Patients who were interested and who consented to having their contact information passed on to the research team were contacted by the lead research assistant. The research assistant answered patients’ questions and, if they were still interested, set up a time for the interview. Written and/or verbal informed consent was obtained.
Snowball sampling was used to identify stroke physiatrists from across Canada; potential participants were approached with an information sheet by email. To ensure diversity of viewpoints, we asked the participants to refer physicians who may have differing opinions.
Research assistants with backgrounds in health science were trained in conducting interviews, and using the TDF to inform data collection and analysis. Research assistants conducted all interviews by phone or in person at the rehabilitation centre (PJ, WT, AC and JZ). Participants could be accompanied by a caregiver (family or friend) during the interview if they preferred. Sample sizes were determined using a 10+3 stopping rule.20 After 13 interviews were conducted, data were considered adequate if no new themes emerged within the last three consecutive interviews.
Semistructured interview guides were used, and participants were encouraged to expand on their answers. At the beginning of the interview, the research assistant explained to patients and physicians current evidence regarding MSCs in treating subacute and chronic stroke. They also described the potential mechanisms of action and noted that we are only just beginning to learn about the different benefits and risks; however, existing clinical evidence suggests this therapy may be safe. The research assistant then explained that our team plans to conduct an early phase trial, in which the main goal is to confirm that MSCs are safe. All interviews were recorded, transcribed and pseudonymised.
Using NVivo 10 (QSR International, Australia) a directed content analysis was conducted.21 Consistent with guidance published by Atkins et al,13 analysis was led by a primary analyst who coded each interview transcript by selecting relevant excerpts and assigning them to one of the theoretical domains from TDF version 2 (WT and AC).16 A secondary analyst, blinded to the primary researcher’s assignments, subsequently coded the selections to TDF domains (JZ and YYD). Conflicts were resolved through discussion or a senior investigator (JP and ML). Two pilot interviews were coded and used to develop a common coding strategy to ensure consistency. The final coding strategy was developed with oversight by a researcher experienced in application of the methods used (JP).
Generation of belief statements and identification of relevant domains
All excerpts coded into a TDF domain (ie, from across all interviews) were examined to identify key underlying beliefs and generate belief statements.22 Relevant domains were identified based on: (1) the frequency with which a belief was mentioned by different participants, (2) the presence of opposing beliefs and (3) evidence of strong beliefs in a domain that may impact decisions to participate in a clinical trial of MSC therapy for chronic stroke.22 23 Overarching themes spanning the relevant domains were then generated.
Patient sample characteristics
Twenty-four patients were approached and 13 agreed to participate in semistructured interviews; all interviews were completed over the phone (table 2). Participants (10 male, 3 female) had a median age of 67 (range 25–79). Two patients had experienced more than one stroke. Interviews ranged in duration from 17 min to 37 min, with a median interview time of 25 min. Data adequacy was reached after the 13th interview.20
Physician participant characteristics
A total of 40 Canadian stroke physicians were approached and 15 participated in semistructured interviews (spanning Canadian provinces of British Colombia, Alberta, Manitoba, Ontario and Nova Scotia). Fourteen interviews were conducted over the phone, while one was conducted in-person. Of these, 13 interviews were fully coded and included here as data adequacy was reached as per our predefined sample size rule.20 Physicians (seven male, six female) had been practising for 3–35 years, and a median of 25% of patients in their practices had chronic stroke (range=5%–60%) (table 3). Median interview time for physicians was 25 min (range 15–31 min).
Key themes identified from patient interviews
Patient key theme 1: patients are optimistic and perceive potential benefits to participating in an MSC therapy trial (optimism, beliefs about consequences, social/professional role and identity, intention, beliefs about capabilities and goals)
Almost all patients were optimistic that participating in an MSC therapy trial for chronic stroke would result in more good things than bad. Some patients expressed that an efficacy trial may directly benefit them as well as others in the future. All interviewed patients identified that health benefits (eg, ‘to get better’, reverse the damage, symptom reduction and prevention of future strokes) and/or functional improvement would be an important goal of participating in the trial.
Most patients said they would consider enrolling in the trial if one were to be available in the next year and most also said that they would feel confident in their ability to enrol and/or participate. Interestingly, almost all patients expressed that the prospect of a placebo group would not affect their decision to participate in a negative way. Some patients reasoned that this would still allow them the chance to receive therapy, as compared with not participating at all.
Well to me, I’m already in the non-treatment group. So, the only thing that would be different is that I could be in the treatment group.- Patient 5
Patient key theme 2: patients have some concerns about risks, uncertainty and safety (beliefs about consequences, intention and emotion)
Although several patients stated that they did not think the trial would have any negative aspects, most patients did express concern regarding the potential side effects of MSCs. Some patients also voiced that they were unsure of what the consequences or benefits would be. However, there were opposing views as to whether a safety (vs efficacy) trial would affect their intention to participate. Almost half of those interviewed said their motivation would not be affected if the purpose of the study was to assess safety rather than efficacy. In contrast, some patients expressed that they would be less motivated to participate in a safety trial.
I would be not very motivated if it was just to check the safety of it. Because it’s saying, wow…that you’re really a guinea pig …. - Patient 10
Several patients also expressed that the method of administration would affect their decision to participate in the trial (ie, intravascular preferred over intracerebrally).
Patient key theme 3: patients want more information and resources
Almost all interviewed patients expressed limited knowledge of MSCs and suggested they would require more information on risks and benefits of MSCs and available alternative therapies. The majority of patients did not have any moral or ethical issues with the idea of ‘stem cells’. Several patients noted that logistical factors, such as location and time considerations, would weigh into their decision to participate. A majority also identified transportation or financial reimbursement as key resources to enable participation. Only one patient felt that they would not require any additional resources to participate.
Patient key theme 4: physicians, researchers and family would influence intention to participate (social influences)
Almost all patients identified that opinions of researchers and their physicians or family would impact their decision to participate. When asked how they would go about enrolling in a clinical trial, almost half of the patients interviewed stated that they would enrol through their physician; however, several mentioned they would respond to other sources (eg, newspaper and online advertisements).
Key themes identified from physician interviews
Physician key theme 1: physicians feel capable and motivated
Almost all physicians interviewed were generally optimistic that a trial to assess MSC therapy for chronic stroke would provide several benefits for both patients and themselves. All physicians said they would consider participating in the trial if available in the next year and most physicians said they would feel confident in their ability to screen or refer patients for the trial.
Physician key theme 2: concerns about risks, uncertainty, safety and the need for more information about MSCs (beliefs about consequences, intention and knowledge)
Specific knowledge on MSCs varied across physicians; one explicitly expressed that they ‘don’t know anything about [MSCs]’ (Physician 7), while most reported awareness or some knowledge of cell therapy. Most physicians expressed that there may be disadvantages to patients or that they were unsure of the consequences of treating patients with MSCs. Similarly, most physicians reported that the safety of MSCs would play a large role in their decision to screen for the trial.
I would like to know that … the safety issue has been sorted out so that I can say to mypatients, ‘It has been shown that they are safe’.- Physician 3
Similar to patients, there were conflicting views as to whether the primary goal of the trial (safety vs efficacy) would affect their motivation to become involved; most expressed that they would still be motivated to screen for a safety trial, although some physicians expressed that they would be less motivated. Physicians who suggested their motivation would be decreased also noted, however, that they understood these types of trials need to be completed.
Physician key theme 3: involvement aligns with professional role but resources are needed
Although most physicians agreed that being involved in a cell therapy trial could be a part of their professional role, a few also expressed concern that screening their own patients may result in bias or patients feeling pressured to participate. Many potential barriers to physicians’ involvement in the trial were identified. All physicians stated that they would require additional time and resources to participate. Every physician suggested that screening would add to their workload and associated stress levels, though to varying degrees. Most of the physicians suggested that additional staff to screen and help coordinate ongoing care would ameliorate these stresses and concerns. Other additional resources were also frequently mentioned including background material, information to relay to patients, education and training, and costs to cover such training.
Physician key theme 4: colleagues and researchers may influence physicians’ participation (social influences)
Most physicians expressed that the opinions of colleagues, other physicians and researchers would impact their decision to participate. A small proportion also noted that those running the trial would influence their decision to participate; in particular, trusting the principal investigator was important.
The findings from this study point to several key considerations that will influence the development of a feasible clinical trial protocol. Our study is novel in that it assessed these views in a comprehensive manner prior to initiating a resource-intensive cell therapy trial. This is in contrast to a previous retrospective narrative that detailed encountered barriers to cell therapy trials for stroke.11 We detail key findings and potential implications for future clinical trials.
There has been little work assessing potential barriers and enablers to both patient participation and physician involvement in early phase clinical trials. This is an important knowledge gap as considerations to take part in such trials may differ substantially from those to take part in a later phase trial where safety is better established and trial outcomes focus on measuring benefits. Encouragingly, both patients and physicians showed interest in an MSC therapy trial for chronic stroke. This is an important finding as previous studies have found that investigators may overestimate enthusiasm for experimental trials.24 25 Within the domain of chronic stroke therapy, however, we found a clear appetite for studies evaluating stem cell therapy.
Safety of the therapy was an important issue to both patients and physicians. Our finding is consistent with two previous systematic reviews9 10 that identified concern of the uncertainty surrounding trials as a commonly cited barrier to patient participation. These reviews also identified physicians’ ‘concern for patients’9 or ‘gate keeping on behalf of the patients’10 as potential barriers. When considering future clinical trials of MSC therapy, physicians may benefit from receiving clear information on the safety of MSCs (eg, systematic review).26 This may help to increase physician comfort and confidence. Patients may similarly benefit from further information on the safety of MSCs; however, further work is required to determine how best to convey this information to patients.
Perhaps surprisingly, almost all patients expressed that inclusion of a placebo group would not impact their decision to participate. This is contrary to previous literature that has reported randomisation as a potential barrier to patient recruitment.9 10 27 28 Our finding may reflect the fact that chronic stroke is an under-researched area1 and, as a result, there is a strong appetite among patients to participate in evaluations of promising new therapies. This finding underscores the importance of conducting trial specific assessments and not assuming patient barriers. Based on our findings, randomised controlled trials or cross-over cell therapy trials may be attractive study designs for some chronic stroke patients.
Our interviews with patients also allowed us to identify important patient considerations and preferences. A recent review on the use of cell therapy for treatment of stroke highlighted that patients sometimes have ethical concerns with ‘stem cells’.11 Patients may mistakenly believe that stem cells can only be procured from embryos,11 while in reality they can be collected from other sources (eg, bone marrow). Counter to this, our interview study found that only one patient voiced ethical concerns over the use of stem cell therapy.
All interviewed patients identified that health benefits and/or functional improvement would be an important goal for the trial. This finding may help guide selection of outcomes in clinical trials to help ensure the data collected is of interest to patients. Many patients also voiced that the method of MSC administration would affect their decision to participate. Thus, offering the preferred route of administration in a clinical trial may attract more patients to enrol. Furthermore, similar to previous reviews,9 10 providing support to address logistical issues, such as transportation, was identified as a potential enabler. Allocating funds to ensure patients have appropriate transportation and additional living costs may be an important consideration for future trials.
Despite physicians’ interest in an MSC trial, many potential barriers to their involvement were identified. Some of these barriers have been identified in previous publications. For instance, concerns regarding time and recruitment’s effects on relationships with patients have been identified as physician barriers,9 10 as well as insufficient training and limited availability of staff.9
Our study provides an overview of factors that may influence participation in a planned early phase clinical trial of MSC therapy for stroke. These findings address an important gap in the literature, as previous reviews have focused on barriers and enablers of late phase trials.9 10 Another strength is that our interview guide was developed from the TDF, which encompasses a broad range of theoretical perspectives.12 16
Our study has limitations that should be considered. Those who participated may be generally more open to research and may hold different views compared with those who declined to participate. Furthermore, patient participants may have been more likely to be from a higher socioeconomic position (SEP)29–32; their barriers may differ from those of a sample with lower SEP. Patients within our sample also tended to be of older age and male. However, we anticipated that most patients would be of older age, as age is a risk factor for stroke.33 Future studies should aim to recruit a balanced sample of both males and females, as well as measure SEP and educational level to better describe the study population. Another limitation of our study is that only English-speaking participants were included. Future studies investigating perspectives in other languages will be valuable and important for trial recruitment from an equity of access perspective. An alternative study design (such as a survey) may be needed to confirm our results in a broader sample13; however, because this was a relatively novel topic, we conducted a comprehensive interview study to elicit discussion and understanding.
Application of the TDF was valuable in identifying potential barriers and enablers to trial participation from the perspective of two key stakeholders: patients and clinicians. By engaging directly with patients, we were able to identify their preferences in terms of the method of administration, support, and trial outcomes. Interviews with physicians also yielded important information on their training and resource needs. Findings of this study will help refine the design and conduct of our planned MSC therapy trial.
Our approach also helps to build on existing literature of perceived barriers and enablers to early phase clinical trials; some of these findings may be transferrable to other trials. Investigators conducting future early phase cell therapy trials should consider the importance of developing clear information on the safety of the therapy for both physicians and patients; moreover, codevelopment of these educational materials may ensure that particular concerns are addressed in a comprehensive and understandable manner. Additionally, as both physicians and family members were found to be important social influences in a patient’s decision to participate, this should be considered when designing the recruitment approach. Our findings suggest that arranging for physicians to be available to discuss the trial with patients and their caregivers would be helpful. More generally, the methodological approach taken, which draws on a comprehensive framework of factors that may influence decisions, motivation and ultimately action (in this case, participating in and conducting a cell therapy trial), may itself be a valuable approach to inform and optimise other future similar trials.
We found this qualitative approach valuable in confirming interest for the trial. Study findings also showed us that participant barriers should not be assumed and that rather patients should be asked and involved. Despite researchers suggesting potential concerns,11 we found that patients did not have ethical concerns surrounding the use of stem cells, nor would a placebo necessarily deter them from participating. We encourage other investigators to take this approach when developing future trials to identify barriers and enablers a priori, as this will help to improve the design of the trial to better meet the needs of both patients and physicians.
The authors would like to thank the patients and physicians for volunteering their time to participate in this study.
MML and MF contributed equally.
Contributors MML and DAF: conception and design, methodology, provision of study material, manuscript writing and supervision. MF: data analysis and interpretation and manuscript writing. JP and DD: conception and design, methodology, provision of study material and manuscript writing. GC: manuscript writing. AC, JZ and YYD: collection and assembly of data, data analysis and interpretation and manuscript writing. WT: collection and assembly of data, data analysis and interpretation. DT: provision of study patients and manuscript writing. PJ: collection and assembly of data and final approval of manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval Ethics approval was obtained from the Ottawa Health Science Network Research Ethics Board (20160708–01H) and the Pembroke Regional Hospital.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request. The data that support the findings of this study are available from the corresponding author on reasonable request.
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