Abstract
Background aims
Early-phase cell therapy clinical trials depend on patient and physician involvement, yet barriers can impede their participation.
Methods
To optimize engagement for a planned cell therapy trial to prevent perioperative cardiac complications, the authors conducted semi-structured interviews with at-risk patients and physicians who could potentially be involved in the study. The authors used the theoretical domains framework to systematically identify potential barriers and enablers.
Results
Forty-one interviews were conducted to reach data saturation, and four overall potential barriers to participation (themes) were identified. Theme 1 emphasizes that patients and physicians need accessible information to better understand the benefits and risks of the novel therapy and trial procedures and to address misconceptions. Theme 2 underscores the need for clarity on whether the trial's primary purpose is safety or efficacy, as this may influence patient and physician decisions. Theme 3 recognizes the resource and logistic realities for patients (e.g., convenient follow-up appointments) and physicians (e.g., personnel to assist in trial procedures, competing priorities). Theme 4 describes the importance of social influences (e.g., physicians and family, peers/colleagues) that may affect decisions to participate and the importance of patient preferences (e.g., availability of physicians to discuss the trial, including caregivers in discussions).
Conclusions
Prospectively addressing these issues may help optimize feasibility prior to conducting an expensive, resource-intensive trial.
Key Words
Introduction
A number of reports have identified barriers to patient participation and physician involvement in clinical trials, though few focus specifically on early-phase trials [
1
, 2
, 3
, 4
, 5
, 6
]. Commonly cited patient-related barriers include concerns regarding potential treatment risks, uncertainty over treatment outcomes, trial burden, logistics (transportation, time commitment), financial implications, not wanting to be randomized, treatment preference and needing more information [1
, 2
, 3
, 4
, 5
,[7]
]. The context of when patients are asked to participate (e.g., after being given a diagnosis), social influences (e.g., family, physician) and distrust or wariness of research may also influence participation [1
, 2
, 3
, 4
, 5
]. In addition, prominent barriers to physician involvement in clinical trials include resource constraints, potential for adverse effects, worry of harming the physician-patient relationship, difficulty with protocol execution and disagreement with study design, relevance or rationale [[1]
,4
, 5
, 6
].The authors’ team will be conducting an early-phase clinical trial to assess the safety and efficacy of mesenchymal stromal cells (MSCs) for the prevention of cardiac complications after non-cardiac surgery. The trial will recruit patients undergoing an intermediate- to high-risk non-cardiac surgery who are at increased risk of perioperative cardiac complications [
[8]
]. Although MSCs have been assessed in clinical trials for safety and efficacy in treating ischemic heart failure and acute myocardial infarction [[9]
], this will be the first clinical study to assess MSCs as a therapy for the prevention of perioperative cardiac complications.The Clinical Trials Transformation Initiative has encouraged transforming the way clinical trials are planned to assess feasibility and ensure success [
[10]
] and suggests involving key stakeholders such as patients and clinicians in the trial development process to “produce greater impact and reduce downstream barriers.” Thus, before embarking on an expensive and resource-intensive early-phase perioperative cell therapy trial, the authors undertook a theory-driven interview study to identify hypothetical barriers and enablers to patient participation and physician involvement (where patients and physicians were asked to consider hypothetically taking part in the planned trial) [11
, 12
, 13
]. Identified potential concerns and considerations could then aim to be addressed when developing the trial protocol. The authors also used the comprehensive theoretical domains framework (TDF) [[11]
,[12]
], which encompasses 33 theories related to behaviour and behaviour change, organized into 14 high level domains. This framework has been widely used to study determinants of behavior and has demonstrated success in identifying implementation barriers and enablers across various contexts [13
, 14
, 15
, 16
, 17
, 18
]. The authors chose to apply the TDF using semi-structured interviews in order to explore potential barriers and enablers in-depth through open questions and probes. This study design allowed the authors to explain details of the planned trial, to obtain direct input from key stakeholders on this novel topic (hypothetical participation in an early phase, perioperative, cell therapy trial), and to explore participants’ feelings and beliefs. Using the findings from this study, the authors have developed a patient- and physician-centered trial protocol that aligns with these stakeholders’ needs and preferences to help overcome identified potential barriers. The authors believe this approach could be adopted by other teams aiming to optimize the design and conduct of cell therapy clinical trials.Methods
Ethics
Ethics approval was obtained at three institutions (The Ottawa Hospital, St. Michael's Hospital and Hamilton Health Sciences) through the streamlined Clinical Trials Ontario Research Ethics Board system (project identifier, 1424, Ottawa Health Science Network Research Ethics Board [University of Ottawa Heart Institute Panel], protocol identifier, 20180358-01T). The study protocol was also registered and can be accessed through the Open Science Framework (https://osf.io/2wdcf). This study has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans. Informed consent was obtained for experimentation with human subjects (written informed consent was obtained from all participants). The privacy rights of human subjects were observed. The study is reported in accordance with the consolidated criteria for reporting qualitative research [
[19]
] and the guidance for reporting patient and public involvement, version 2, short form (see supplementary Files 1,2) [[20]
].Theoretical domains framework
The authors developed an interview guide based on the TDF [
[11]
,[12]
], which outlines a consensus-based set of key factors that inform decision-making and behavior. The TDF is well established in implementation research, most typically to investigate implementation barriers and enablers, to inform the development of interventions and to develop process evaluations [[13]
,[17]
,[18]
]. Recently, the authors’ team and collaborators used the TDF to investigate barriers and enablers to patient participation and clinician involvement in early-phase clinical trials [[15]
,[16]
,[21]
,[22]
].Interview guide development
The authors’ team identified three core populations who would be required to make decisions and changes in behaviour (e.g. “who needs to do what differently” [
[23]
]) that would be critical to the success of the planned cell therapy trial. This included: (i) patients undergoing intermediate to high risk surgery, at risk for perioperative cardiac complications who would potentially meet eligibility criteria for the planned trial, (ii) anesthesiologists who would administer the MSC product and provide extended postoperative monitoring of these patients, and (iii) cardiologists and perioperative general internal medicine physicians who would provide care to these patients post-operatively (in-hospital as well as follow-up outpatient appointments). As use of MSCs for the prevention of perioperative myocardial infarction is a novel application, the authors were uncertain of their stakeholders’ views on use of such a therapy and willingness to participate or be involved in such a trial. The authors were thus interested in exploring their perspectives. The specifics of these behaviors are outlined in Table 1, as suggested by the action, actor, context, target, time framework [[23]
]. The authors adapted TDF interview guides to assess these three behaviors. In brief, these semi-structured interview guides included at least one question for each of the theoretical domains in TDF (version 2) [[12]
] as well as the TDF nature of behavior domain (version 1) [[11]
]. After participants were asked about their existing knowledge of MSCs and what they perceived to be positive/negative aspects of hypothetically participating in the trial, a short, non-technical summary describing the results from the authors’ team's systematic review (with regard to assessing MSCs for the treatment of ischemic heart failure and acute myocardial infarction) was read to participants. Full interview guides can be accessed in supplementary Files 3–5; interview guides were designed to be adaptable for other trials and settings. The interview guide for patients was piloted with two patient partners to refine the wording of questions and prompts.Table 1Specification of the behaviour using the Action, Actor, Context, Target of Behaviour, and Time (AACTT) framework.
| Actor | Patients at higher risk of cardiac complications, undergoing intermediate to high risk surgery | Anesthesiologists | Cardiologists & General Internists |
|---|---|---|---|
| Action | Decision to enroll and participate in an MSC clinical trial. Participating in the trial would entail: 1) Receiving MSC therapy at the beginning of surgery 2) Attending follow-up appointments | Administration of MSCs (IV, slow infusion) before or after induction of anesthesia (prior to surgical incision) Post-operative monitoring in the post-anesthesia care unit (likely extended stay of 6 hours and sign out) | Providing follow-up care during hospital stay and conducting follow-up outpatient appointments |
| Context | Hospital; when undergoing intermediate to high-risk surgery | Hospital (operating room & post-anesthesia care unit) | Hospital and outpatient clinic |
| Target of behaviour | Patients at higher risk of cardiac complications after surgery (e.g. participate in the trial and receive MSC therapy/ attend follow-up appointments) | Patients at higher risk of cardiac complications after surgery (e.g. receive MSC therapy administered by anesthesiologist) | Patients at higher risk of cardiac complications after surgery (e.g. receive post-operative care from cardiologists and general internal medicine physicians) |
| Time | Prior to surgery and throughout the clinical trial (length to be determined, but potentially includes follow-up appointments at 1 week, 1 month, 6 months, and 1 year post, plus phone calls monthly for the first year, and annually for 10 years to collect registry data) | Throughout clinical trial (length to be determined) Would administer therapy before or after induction of anesthesia (prior to surgical incision) for each patient and post-operatively monitor for 6 hours after surgery | Throughout clinical trial (length to be determined, but potentially includes follow-up appointments at 1 week, 1 month, 6 months, and 1 year post, plus phone calls monthly for the first year, and annually for 10 years to collect registry data) |
MSC = mesenchymal stromal cell.
Sample size
The 10 + 3 rule was used to determine the sample size for each stakeholder group [
[24]
]. The authors started by conducting a minimum of 13 interviews for each group. Once no new themes had emerged within the last three consecutive interviews, sample data adequacy was deemed appropriate to sufficiently describe important barriers and enablers to patient participation and physician involvement in the planned cell therapy trial.Patient recruitment
As behaviour and behaviour change can be influenced by context [
[13]
], the authors aimed to speak with populations who would most closely resemble those being approached for the eventual trial. Patients were recruited from pre-admission units at two urban tertiary care centers (three campuses) in Ontario, Canada, approximately 1 day to 3 weeks before their scheduled surgery. Patients with an increased risk of cardiac complications after surgery (over 45 years old with a revised cardiac risk index [[8]
] of ≥2) were recruited to participate. These higher-risk patients represented the potential target population of the authors’ future interventional clinical trial. Participants could choose whether to complete the interview that same day in person or at a later date over the phone at a time most convenient for them before their upcoming surgery.Physician recruitment
Physicians were recruited from three urban tertiary care centers (four campuses) located within Ontario, Canada. Recruitment e-mails were sent by the study investigators to anesthesiologists, cardiologists and perioperative internal medicine physicians at each of the potential trial sites. Participants were also subsequently asked to refer additional physicians who might be interested in participating (cf. snowball sampling). Interviews were conducted in person or over the phone.
Patient partner involvement
Throughout this project, the authors’ team worked with three patient partners (recruited to the team through the patient and family engagement organization at the first author's hospital) with lived experience of undergoing surgery or caring for a loved one who had undergone surgery. These partnerships aimed to ensure that the interview questions were accessible and that patient perspectives were integrated into the authors’ study. Two of the patient partners, one with expertise in linguistics, helped the authors’ research assistants complete practice interviews and provided feedback on the language of the patient interview guide. The third patient partner, who is also a communications specialist, provided their perspective on the interview study results and provided critical input on the manuscript.
Interview procedure and data analysis
Research assistants (MF, AC), who were trained by a qualitative researcher (JP), conducted the interviews using the semi-structured interview guides. Prompts were used when needed to encourage elaboration of responses. Interviews were audio-recorded and transcribed verbatim by research assistants. Interview transcripts were pseudonymized and uploaded into the qualitative software NVivo 11 (QSR International, Doncaster, Australia). All interviews were analyzed in duplicate by research assistants working independently (MF, TH). A directed content analysis [
[25]
] was conducted in which analysts assigned interview text to TDF version 2 domains [[12]
] as well as the nature of behavior domain from TDF version 1 [[11]
]. Consensus meetings were held to resolve conflicts. Global themes were then identified across both populations by one research assistant (MF) with input from one patient partner (JY) and the research team through a four-step process:- (i)Within each domain for each population, similar quotes were grouped together and assigned a belief statement (i.e., a representative summary statement) to identify key domain-specific themes.
- (ii)Relevant domains for each population were then identified based on three core criteria as per Patey et al. [[26]]—frequent, contrasting or strong belief statements (i.e., factors appearing to influence the behavior of interest in an important way).
- (iii)Global themes for each population were developed by grouping together related key themes across domains.
- (iv)Global themes were identified by looking for similarities across population-specific global themes.
Results
A total of 41 in-depth interviews were completed to reach data saturation (i.e., no additional issues or insights emerged from the data); 13 patients and 28 physicians (13 anesthesiologists and 15 consulting cardiologists/internists) participated. The patient and physician populations are described in Table 2A,B. Four global themes were identified across the participant populations, spanning 10 of the 15 domains in the TDF (relevant TDF domains denoted in parentheses):
- (i)Need for accessible information to better understand the benefits and risks of the novel therapy and trial procedures and to address misconceptions (knowledge, beliefs about consequences, goals, optimism).
- (ii)Trial design may affect intention to participate (intention; e.g., safety versus efficacy).
- (iii)Additional personnel and convenient appointments required to address competing physician priorities and logistical barriers (beliefs about capabilities, environmental context and resources, goals, nature of behavior, social/professional role and identity).
- (iv)Patients highly value the opinion of physicians and family; physicians value peer/colleague support (social influences, social/professional role and identity).
Table 2aPatient participant demographics.
| Characteristic | Patients |
|---|---|
| Number of participants | 13 |
| Sex | |
| Male | 9 |
| Female | 4 |
| City | |
| Ottawa | 12 |
| Toronto | 1 |
| Hamilton | 0 |
| Median revised cardiac risk index (range) | 2 (2–3) |
| Median days until surgery (range) | 7 (1–18) |
| Caregiver present at interview | 8 |
| In-person interview | 8 |
| Phone interview | 5 |
| Median interview length, min (range) | 24 (16–47) |
| Median age, years (range) | 71 (55–88) |
Table 2bPhysician participant demographics.
| Characteristic | Anesthesiologists | Cardiologists and internists |
|---|---|---|
| Number of participants | 13 | 15 |
| Sex | ||
| Male | 9 | 11 |
| Female | 4 | 4 |
| City | ||
| Ottawa | 7 | 5 |
| Toronto | 2 | 2 |
| Hamilton | 4 | 8 |
| Prior clinical trial experience | 12 | 14 |
| In-person interview | 2 | 1 |
| Phone interview | 11 | 14 |
| Median interview length, min (range) | 35 (25–54) | 40 (27–53) |
| Median time since medical degree, years (range) | 18 (7–24) | 17 (6–33) |
Global themes and a subset of illustrative quotes are depicted in Table 3A–D. The number of coded sections of text for each population by domain (and number of participants) was also extracted (see supplementary File 6).
Table 3aGlobal theme 1: need for accessible information to better understand the benefits and risks of the novel therapy and trial procedures and to address misconceptions.
| Subtheme | Illustrative quote | Theoretical domain |
|---|---|---|
| Need for more information | Well, again, I would need more information. . . . I don't know enough about it. I'd like to talk to somebody that does and explain it a little bit more. —Patient 2 Second thing would be to have a sense of what the risks and benefits are. —Anesthesiologist 1 | Knowledge |
| Benefits and risks will influence | I guess it would be a little constellation of factors. Does it add to risk? Does it increase probability of success? —Patient 8 If the balance between the risk and the benefit is okay and if it's not too much load of work without compensation, I think most of the people will be on board. —Anesthesiologist 8 | Beliefs about Consequences |
| Participating may have possible benefits | Because, again, there are high-risk surgeries, which I'm about to undergo. And if something like stem cells could reduce that risk, I would accept it, of course. —Patient 1 Yeah, I think so. If it helps somebody down the road, maybe not for me, but I'd like to help if I could. —Patient 2 I think the most important factor influencing participation is the possibility of participating in something that could dramatically change patient care and patient outcomes. —Cardiologist 1 It's always worthwhile, advancing science and knowledge in this area. —Cardiologist 8 Also, being a part of a perioperative research group, the congeniality of being a part of a research group. —Internal Medicine 5 | |
| Participating may have possible disadvantages | Making a mistake and not being as successful as I thought it would be and maybe getting a shorter life span instead of a longer one, taking away some of my quality of life. —Patient 9 I suppose the time involved. If there are going to be long follow-up interviews, etc., it sort of adds to the amount of time you need to spend dealing with it. —Patient 8 And would the therapy be potentially invasive in its delivery, having the potential to harm in the process? That would be a disadvantage, for sure. —Cardiologist 3 We are perpetually being asked to do more with less and have fewer resources to look after sicker patients, and in that climate you're asking an additional level of involvement, which I think is a disadvantage to most clinicians. —Anesthesiologist 6 Mostly we don't have the resources to keep patients that long . . . so cost-wise that would be too expensive and may not be acceptable to our PACU. —Anesthesiologist 12 |
PACU, post-anesthesia care unit.
Table 3bGlobal theme 1: need for accessible information to better understand the benefits and risks of the novel therapy and trial procedures and to address misconceptions.
| Subtheme | Illustrative quote | Theoretical domain |
|---|---|---|
| Weighing the consequences (Based on the systematic review summary, do you think the benefits outweigh the harms?) | Yeah, I think the benefits will be higher. —Anesthesiologist 10 Um, it's hard to say. I think there's no harm in proceeding and investing [in] it further. —Anesthesiologist 7 Um, sure. Slightly, as is presented. Yep. —Internal Medicine 7 It sounds like it from what you told me, but I prefer to kind of read through the studies on my own. —Internal Medicine 1 I mean, there seemingly are not harms, which probably is the most important bit, but as far as benefits . . . benefiting a non-patient important outcome always comes as an important question. —Internal Medicine 6 Oh, well, we don't know that. If we knew that we wouldn't have to perform the study. But I think that it's encouraging data. —Cardiologist 4 I'm not convinced yet because I think it's too primitive or premature. —Cardiologist 3 | Beliefs about consequences |
| Physician concerns and misconceptions to be addressed | And then obviously the biggest issue with any cell-based therapy trial is the safety profile. You know, making certain that the cells themselves don't do any harm in the long term. —Cardiologist 5 Then I will make some reservation [sic] about the way risk is defined because we don't want to give some treatment with potential deleterious effect, for patients that don't have a true risk, or if they're considered at risk it's not balanced by the benefit of the treatment. —Anesthesiologist 8 How many people would need to be enrolled to find a significant difference? That might affect my willingness to do it. Like if I heard it was a really big number to find an expected difference of 20% or something like that, then I would see that as a pretty futile, expensive and never-going-to-be-incorporated-into-a-standard-of-care intervention. —Anesthesiologist 13 I think that I am quite worried instituting a therapy that has a fundamental question about the, sort of, support for the therapy. Again, that a single researcher who has laid out, sort of, an evidence base in heart failure studies is now being called into question. —Anesthesiologist 13 | Knowledge, beliefs about consequences, goals |
| Potential for therapeutic misconception | [Do you think that participating in a trial, hypothetically, will result in more good things than bad?] Absolutely, yes. —Patient 4 | Optimism |
| Well, for the exact reasons you just read. For improvement of the flow and the heart and strength of it and all that. For sure. —Patient 6 [And how motivated would you be to participate in this study if its goal was to test safety of the stem cells instead of... if stem cell therapy improved your health?] If it improves my health, why not? —Patient 3 If it were available today and if I had any notion that it might help me in my healing process and reduce the risk of the high-risk operation that I'm about to have, I would accept it gladly. —Patient 1 | Goals |
Table 3cGlobal theme 2: trial design may affect intention to participate.
| Subtheme | Illustrative quote | Theoretical domain |
|---|---|---|
| General intention | [So would you participate in a stem cell therapy for the prevention of cardiac complications after surgery if one was available now?] Yes. —Patient 6 [Would you participate in this trial if one was available now?] Right now? No. —Patient 4 [Would you agree to administer MSCs and monitor patients postoperatively in the PACU if one is available in the next 2 years? A clinical trial like this one?] Yes, I would. —Anesthesiologist 3 Ah, well, I would consider it. . . . It would all depend on my [other] commitments that are ongoing at the time. —Internal Medicine 6 [And would you agree to provide in-hospital follow-up care and conduct follow-up appointments for patients as part of a trial of MSCs for prevention of [perioperative myocardial infarction] if one is available in the next 2 years?] Ah, at this point I would say no. —Internal Medicine 7 | Intention |
| “Usual care group” | [And how would the possibility of the placebo control—so, the usual care group—affect your motivation?] I think that I'd be fine with it. I don't think it would affect it one way or another. —Patient 13 Well, I wouldn't know, so I'd be taking a 50/50 risk that I would qualify for the stem cells rather than the placebo. [Would that make you less inclined to want to participate?] Yes. —Patient 9 | |
| Safety versus efficacy trial | [How motivated would you be to participate if the goal of this study was to test if the stem cells were safe and not to test if the stem cells improved your health?] Oh, I'd give it a try. —Patient 11 I think probably less inclined if it was testing safety because, of course, you'd like to feel that safety was established before you participated. —Patient 8 [How motivated would you be to become involved in a trial of MSCs if its goal is to test the safety but not efficacy?] Very. Very motivated. It is the first step before the efficacy test, so it makes sense. —Anesthesiologist 7 Ah, I would say interested, but I'd prefer once that safety has been proven to be part of that study. —Internal Medicine 5 [And how motivated would you be to become involved in a trial of MSCs if its goal was to test the safety of MSCs but not the efficacy?] Um, less motivated, because it sounds like that's already, you know, largely been done in other contexts. —Internal Medicine 2 |
PACU, post-anesthesia care unit.
Table 3dGlobal theme 3: additional personnel and convenient appointments required to address competing physician priorities and logistical barriers.
| Subtheme | Illustrative quote | Theoretical domain |
|---|---|---|
| Ability/capacity to participate, competing priorities and additional contextual factors | I'm going to say, because of where I live, impossible. To be honest with you. I really feel that, I mean I really believe in all this. . . . I just, taking so much time off work right now in a new job, and it's just, yeah. —Patient 4 I think the workload involved would probably be the most important factor. So if it's, you know, an extensive amount of work that's required from us, it can be very challenging to do that in our current clinical setting. —Anesthesiologist 4 | Beliefs about capabilities, environmental context and resources, goals, nature of behavior |
| Potential barriers/factors in decision to participate | Well, of course parking is expensive as [****] now. You don't go down there for less than 14 dollars, you know, for parking minimum. —Patient 7 Unfortunately, my health restrictions are a factor that . . . I would be gung-ho with it if I was a little younger. —Patient 7 But if it requires staying 6 hours after the patient's done, and you know, you finish your case at the end of the day, are you going to come back at 9 o'clock at night to see the patient? —Anesthesiologist 4 The routine requirement of having to follow up with them on a monthly basis might be challenging as well. —Internal Medicine 6 The other major barrier would be these outpatient follow-ups, in terms of clinic space . . . if you were to add more follow-ups, that would definitely complicate that schedule. —Internal Medicine 1 | Environmental context and resources |
| Context and convenience are key: enablers and helpful resources | You might deal with that by piggybacking that appointment on another one. You know, that could be follow-up appointments with surgeons too. —Patient 8 I think parking is a consideration. —Patient 6 I think a website would be helpful, for sure. —Patient 6 A brochure would help, something written. Something from the doctor, verbal. —Patient 9 I think probably an entire educational program . . . things like primary literature, a webinar, you know, or recorded video lecture . . . the ability for me to [ask] questions. —Anesthesiologist 13 At least a portion of any follow-up visits would be clinical, but over and above that then anyone in my group who is going to participate would expect reimbursement for this. — Cardiologist 2 Funding for if the hospital requires me to provide the space or rooms or administrative support, research assistants, assistance with submitting ethics. —Internal Medicine 4 Having [the cells] delivered, a reminder. —Anesthesiologist 2 But it could be something like, you know, prior to hospital discharge or 1 week post or something like that so it gives a bit of flexibility. —Cardiologist 7 | Environmental context and resources |
| Shared role/team required | If you want to run this as easily as possible you would get a study nurse to actually do all the postoperative monitoring. —Anesthesiologist 9 Are there specific immune or other side effects from the stem cell treatment that need to be addressed, and if so, you need to find someone else to do that. —Cardiologist 2 Yeah, I think it would be very challenging for us, for physicians, for the general internists’ side to do phone calls monthly . . . so some sort of nurse practitioner or research assistant could. —Internal Medicine 1 | Social professional role and identity |
Table 3eGlobal theme 4: patients highly value the opinion of physicians and family; physicians value peer/colleague support.
| Subtheme | Illustrative quote | Theoretical domain |
|---|---|---|
| Patients highly value the opinion of doctors and family | [And from whom would you like to receive more information from? So maybe a doctor or research team personnel? A trained nurse?] A doctor. —Patient 11 Well, I've always trusted doctors, so I'm not sure I would understand if they got into too much technical stuff. But I generally trust doctors because it would be in your best interest. —Patient 7 Perhaps, but there might be an equivalent of a doctor . . . unless it was pretty well established somewhere else. I'd like to hear from a medical professional. —Patient 8 Well, I think once you've got the research it would be family. —Patient 6 My wife would be my most concerned. She would be the one whose opinion I would take above all others. —Patient 7 Well, somebody that's been participating in it or something. —Patient 11 | Social influences |
| Physicians value peer/colleague support | I think the same thing. It would be reassuring as well to know that our cardiology colleagues are also involved and optimistic and supportive as well. And, of course, anesthesia as well. —Internal Medicine 1 [And whose views might have an impact on whether you decide to become involved in this trial?] Well, the people running the trial and the manner in which they present it. —Anesthesiologist 6 | |
| Patient views | No, not at all. I don't see any [moral or ethical issues]. If that part of your anatomy could help someone else, why not? —Patient 7 | Social professional role and identity |
Four Global Themes
Need for accessible information to better understand the benefits and risks of the novel therapy and trial procedures and to address misconceptions
Each participant group expressed that they would require more information on the novel therapy (MSCs). Physicians frequently mentioned that safety of the therapy would be a key consideration and that they would need to review the existing evidence surrounding the therapy. Physicians indicated that the side effects and risks of the therapy as well as the probability of benefits, success or impact of the trial would influence their decision. When asked whether they thought the benefits outweighed the potential harms, physician answers were highly variable, from “yes/probably” (e.g., “the benefits outweigh the potential harms”) to “worth conducting a trial” (e.g., “I do not think the therapy will work, but we will advance knowledge”), “not sure” (e.g., “I need to review the evidence”; “not sure if the benefit will be clinically relevant”) and “no” (e.g., “I'm not convinced; it's too early”). A few physicians noted additional concerns that may influence their decision, such as the need to identify an adequately high-risk population.
Some physician concerns also highlighted potentially important areas for clarification. For instance, one physician worried that studies contributing to the evidence base were under scrutiny for scientific misconduct; however, this concern in fact related to a non-MSC therapy (studies conducted by Piero Anversa [
[27]
]). Similarly, misconceptions of the purpose of early-phase clinical trial design were evident. For instance, one physician noted that a high-risk population would be “absolutely critical to be able to see if this therapy is beneficial or not, if . . . delivering [preoperatively],” whereas another voiced that whether the trial was properly powered would influence their decision to participate. Though these aspects will be important for late-stage efficacy trials, the objective of early-phase (e.g., phase 1/2) clinical trials is to assess the safety and feasibility of the novel therapy in a small number of patients.Knowledge gaps were also noted in patients. Most patients indicated having heard of “stem cells” but knew very little about them and as such said they would want to receive more information about the benefits and risks of the therapy and trial from a physician. The authors also identified more specific information of interest to patients and potential areas of confusion (e.g., whether age or condition would affect eligibility, what participation entailed, time commitment, whether they were donating versus receiving cells, whether the cell therapy had been tested in animals or been approved, what tissue the cells were derived from, where the cells came from geographically, whether a matching donor was required for the cell therapy and whether it was possible to acquire communicable diseases from the cell therapy). Patients often mentioned that the benefits and risks of the therapy would influence their decision to participate. When asked what they thought could be potential benefits to participating in the trial, patients noted improved health or quality of life, reduced risk of cardiac complications or surgery, helping others and advancing medical knowledge. When asked about potential disadvantages, they noted adverse events, time commitment and trial burden. A few patients also indicated that they would be likely to participate in the trial if it was thought to be life-saving (e.g., “If I thought it could save my life”; “If you're dying and there's a chance that this would help, I think any normal person would try it whether they know it or don't know what it's about”) or that they would rely on recommendations or advice from a medical professional. Overall, most patients appeared to be optimistic and said that they hoped or expected that participating in the trial would result in more good things than bad.
Trial design may affect intention to participate
Most patients indicated that they would be interested or consider participating in the trial. When asked how their motivation would change if the primary goal of the trial was to assess safety (rather than testing whether it improved their health), some indicated that they would be less motivated, whereas others said they would still be motivated to participate. Most patients indicated that the chance of being allocated to a “usual care group” (a group in which patients would receive standard care, not the experimental therapy) would not affect their decision to participate.
The majority of physicians also indicated that they would be interested in helping recruit and provide care for participants enrolled in the trial. However, several physicians said they would have less motivation for a trial focused on safety outcomes versus a trial focused on efficacy; one expressed that although they would be interested in participating, they would prefer to wait until after safety had been established. By contrast, another physician expressed that they would be less motivated for a safety trial since they felt safety had already been established in other settings.
Additional personnel and convenient appointments required to address competing physician priorities and logistical barriers
A third reoccurring theme across participant groups was the need for resources to address potential barriers to participation or involvement. Most patients acknowledged potential logistical barriers, including location of the trial, traveling, time commitment required or other obligations, responsibilities or conflicts (e.g., work, vacations, family emergencies, other commitments). A small number of patients indicated that participating in the trial would be impossible because of logistical and health constraints (e.g., existing health condition and treatment making the patient tired and unwell, inability to drive, inability of caregiver to help because of work, inability to take time off work). Some patients also noted health or physical conditions or that being older may affect their ability to attend follow-up appointments and continue participation throughout the entire trial. As a corollary, the notion that “convenience is key” was identified as a subtheme. Making trial appointments as convenient as possible and providing support were consistently found to be important to patients (e.g., aligning appointments with other doctors’ appointments, offering virtual follow-up and providing resources for transportation). A few patients also noted needing time to consider the decision to participate, review information in advance or complete their own research on the therapy.
Physicians mentioned competing priorities, such as clinical care, and noted that the workload or time commitment could influence their decision to participate. Anesthesiologists also identified prolonged monitoring and delayed discharge of trial participants from the post-anesthesia care unit as a potential challenge since the need to be present in the operating room may prevent them from monitoring patients in the post-anesthesia care unit. Creating a shared role with other care providers (e.g., post-anesthesia care unit nurses, anesthesia assistants) and a hand-over process for shift changes and minimizing additional workload and disruption to workflow (e.g., limiting paperwork, providing reminders, offering delivery of the therapy) were suggested as potential enablers. By contrast, although consultant cardiologists and internists generally did not see issues to providing inpatient hospital follow-up care, some noted that the outpatient follow-up visits may be challenging. Inadequate clinic space and personnel were noted as potential barriers (or required resources). Many highlighted the importance of having a strong team to share the workload with as well as assistance from research and administrative personnel (or funding allocated to this).
Both groups (patients and physicians) expressed the need for information resources. Patients expressed interest in receiving information in a variety of formats, including via written materials (e.g., brochure); through a website; verbally with a doctor, nurse, medical professional or the trial team; through an online chat platform; or over the phone. Patients also noted interest in receiving updates throughout the trial and the importance of having access to a phone number to be able to ask questions. Physicians similarly noted a variety of preferred formats, including educational or information sessions (e.g., in-service, presentation, teleconference, webinar, question and answer period, videos, learning modules), website, written information (e.g., concise summary, brochure, handout, package, protocol, e-mail, primary literature, systematic review and meta-analysis, Health Canada recommendations), an app, infographics or a combination of these. A few physicians also noted that a website, videos or visuals could be helpful in relaying information about the trial to patients and that notices or reminders about upcoming participants (e.g., e-mail, notice in patient chart) and updates throughout the trial would be useful.
Patients highly value the opinion of physicians and family; physicians value peer/colleague support
Most patients indicated that they would want to receive further information from physicians (rather than clinical research assistants or similar). A few patient participants also specifically expressed that they would want to receive information on the trial from their surgeon or anesthesiologist (“the doctor that operates,” “the doctor administering the procedure”). In addition, patients felt that their families’ views and opinions would influence their decision to participate. Physicians indicated that the views of their colleagues and peers and the trial investigator or research team would influence their decision to participate. Consulting cardiologists and internists also stressed that taking part in the trial would usually be a group decision and that they would need support from their team. Anesthesiologists similarly noted that buy-in, support and communication with other providers (e.g., post-anesthesia care unit nurses), departments and the institution would be important.
Discussion
The authors’ study aimed to identify potential barriers and enablers to participation in an early-phase perioperative MSC trial from the perspective of high-risk patients themselves as well as physicians who would be involved in providing care to these patients. Using a deductive approach built on a well-established theoretical framework, the authors identified several important considerations to take into account as the clinical trial protocol is developed (Table 4). Other investigators planning early-phase cell therapy or perioperative trials may find the authors’ approach and results useful.
Table 4Influence of interview results on clinical trial protocol.
| Identified theme | Planned trial changes effected by interview study |
|---|---|
| Need for accessible information to better understand the benefits and risks of the novel therapy and trial procedures and to address misconceptions |
|
| Trial design (e.g., safety versus efficacy trial) may affect intention to participate |
|
| Additional personnel and convenient appointments required to address competing physician priorities and logistical barriers |
|
| Patients highly value the opinion of physicians and family; physicians value peer/colleague support |
|
Physicians identified potential areas for clarification of early-phase clinical trials, such as the belief that the trial needs to be appropriately powered or that it will be important to determine whether the therapy is beneficial in this setting. Though these aspects are essential for later-phase trials, the core objective of the planned trial, as with any early-phase clinical trial, will be to assess the feasibility and safety of the novel therapy in a small number of patients. Although this notion may seem obvious, the authors’ findings point to potential misconceptions that may affect buy-in, which will be crucial to address in the planned clinical trial. Similarly, physicians also noted that they would be less motivated for a safety trial since some believed that safety had already been established in other settings, whereas others believed MSCs were potentially too risky. Previous reports have also highlighted the need for specialized training on advanced and regenerative therapies, as well as the potential for physician-hesitancy due to uncertainties surrounding such therapies[
[28]
,[29]
]. These findings point to a potential knowledge gap to be addressed with physicians participating in the trial: although MSCs have proven safe in other clinical settings, their safety in a high-risk perioperative population of patients must still be determined. In addition, another physician expressed concerns regarding the MSC therapy itself, believing that scientific misconduct had reduced confidence in MSC therapy in the clinical setting. Further probing, however, demonstrated that this belief was based on misconduct in studies of a cell therapy unrelated to MSCs [[27]
]. Similar to the authors’ findings here, others have identified physician misconceptions surrounding trial concepts such as randomization and equipoise [[30]
,[31]
]. These identified misconceptions underscore the importance of introducing and describing the trial and existing evidence using credible sources. Moreover, the authors’ results suggest that delivering this information in a transparent manner may ensure that trial physicians are aware of the trial objectives and available clinical evidence to date on MSCs (e.g., by summarizing protocol and MSC risks and benefits in an accessible manner) [[32]
].A few physicians also emphasized the importance of selecting a high-risk population for the trial, noting that this would influence their decision to become involved. This concern led the authors’ team to discuss and evaluate available options to best identify potential participants for the trial and ultimately select the highest-risk patients objectively through natriuretic peptide measurement (Table 3B–E) [
[33]
].For patients, therapeutic misconception was evident wherein patients incorrectly (but perhaps not surprisingly) believed the primary aim of the trial was to improve their own health. This conflation of the goals of research with those of medical care has been well recognized in other spheres of research [
34
, 35
, 36
]. Another knowledge gap identified, and potential barrier to patient participation, related to MSC therapy itself. Similar to physicians, patient participants had many questions and required further clarification about the trial and the therapy. The present approach thus enabled the authors to identify specific information from patients that may help them in their decision. As the aim of the trial (e.g., safety versus efficacy trial) was also found to influence intention to participate, it may be helpful to provide an overview on existing safety data in other areas (e.g., ischemic heart failure, acute myocardial infarction). Though the issue of unproven cell therapies did not arise in the authors interviews, reports in the literature suggest that this may be an area of concern [[37]
,[38]
], and something to further address when providing patients with information on the cell therapy. To address these issues, the authors are currently working with patient partners on the research team to develop patient information resources to ensure information is clear (e.g., a one-page non-technical summary). Similar partnerships by the authors’ group and others have demonstrated benefits in design of trial materials and trial design and conduct (e.g., obtaining perspectives on trial information sheets, conducting performance-based readability testing) [39
, 40
, 41
, 42
, 43
]. The value of engaging patients and patient organizations throughout the translation of cell therapy products has also been highlighted by The International Society for Cellular Therapy Commercialization Committee and their collaborating Patient Advocacy Groups. They identified numerous opportunities for collaboration, such as efforts to communicate with patients on ethical issues (e.g. data sharing), discussing the importance of clinical trials and aiding with recruitment, as well as advocating for accessibility and regulation of products, which may be of interest moving into later phase trials [[44]
].Participants indicated they would need to know more about the trial/MSCs. However, one of the key means by which information is relayed to trial participants is through consent forms. This is problematic since typical consent forms are not accessible, comprehension tends to be low, and participants are susceptible to therapeutic misconception [
[36]
,[45]
]. To ensure trial participants are able to comprehend the information the authors provide, the authors are considering using methods to improve the consent process and participant knowledge. This includes visual consent aids, the “teach-back technique” and formal training of staff conducting the consent discussion to ensure the informed consent process caters to various levels of literacy [[45]
]. Finally, purposeful “scientific reframing” of information provided during the informed consent process may help decrease therapeutic misconception while maintaining willingness to participate [[46]
].In terms of recruitment approach, the authors’ results suggest that a variety of formats may be required to accommodate individual patient and physician preferences (e.g., verbal discussion, paper hard copy, website and/or other electronic resources). When asked who they would like to receive further information from, most patients specifically mentioned a trusted physician (rather than a clinical research assistant or similar). In addition, patients noted the influence that family and caregivers would have on a decision to participate in the trial. These findings underscore the need for physicians to be involved in the recruitment and consent process, potentially through creation of an educational video providing pertinent information on the trial and/or additional “check-ins” during recruitment processes that are usually led by clinical research assistants. Moreover, if possible, these discussions should occur with family and caregivers present.
Other important factors to patients included logistical concerns. This is consistent with prior studies, which have identified extra appointments or medical procedures, need for transportation and potential for financial burden due to payments for care, travel and missing work as core logistical barriers to patient participation in trials [
[1]
,[2]
,[4]
,[5]
]. To address these concerns, the authors plan to align trial follow-up appointments with existing appointments when possible. A similar strategy (“arranging a ‘day out’ to coincide with the clinic visit”) was identified as an enabler to continued participation in a recent interview study assessing perspectives of participants across five trials, who had missed one or more follow-up assessments [[47]
]. The authors also plan to allocate resources to assist with transportation costs. These supports may prove to be especially important for patients at high risk of perioperative complications, who may have existing comorbidities, concerns about energy levels and mobility issues, and patients who may not be able to drive or feel comfortable driving.Overall, the authors’ study shows the importance and value of conducting a comprehensive assessment of potential barriers and enablers for a planned clinical trial, by speaking directly with the stakeholder groups. Had the authors not conducted these comprehensive stakeholder consultations, key issues that are easily addressable would potentially have been missed, which could have led to a less than optimal trial design. Though the TDF is used widely across implementation research to study health care provider behaviors and behavior change [
[13]
], application for the purposes of informing development of a clinical trial is relatively novel. Members of the authors’ team have taken this approach to assess potential barriers to and enablers for trials in several different areas, including individualized temperature-reduced hemodialysis [[14]
], MSC trials for bronchopulmonary dysplasia in neonates [[15]
] and chronic stroke [[16]
] and chimeric antigen receptor T-cell therapy for hematologic malignancies [[21]
,[22]
]. Similar to findings in the authors’ current study, this approach has been successful in identifying modifiable factors to better align trials with patient needs and preferences (e.g., information needs, preferences on who to speak with about the trial, method of therapy administration) as well as potential barriers and resource needs for physicians (e.g., workload and time constraints, additional staff to assist).Limitations
Interviews were chosen for this study as the authors’ aim was to provide an in depth-understanding of patient and physician perspectives. Generalizability of findings is often a concern for those less familiar with qualitative methods; however, it should be noted that these approaches provide phenomenological interpretation of data that are difficult to quantify by the usual reductionist and objective methods prevalent in biomedical research. Indeed, many of the potential issues identified with regard to misconceptions and knowledge gaps only became apparent with further prompting used as part of the semi-structured interview process. In addition, the authors conducted an interview study with population-specific sample sizes in line with the recommended number for reaching data adequacy [
[48]
]. Nonetheless, in the future, perspectives elicited from this study could be confirmed in a larger sample using survey methods. Future interview studies could also investigate potential barriers and enablers to other key stakeholders identified by the current study (eg, Post-Anesthesia Care Unit nurses, surgeons and research assistants), and potentially explore additional related topics (eg, unproven cell therapy interventions).The authors also note that there was potential for selection bias in recruitment of participants. For instance, patients who were more interested in research and faced fewer barriers (e.g. healthier, higher socioeconomic status) may have been more likely to participate. The authors partially addressed this issue by conducting interviews during on-site preoperative assessments while the patients were waiting between appointments (or alternatively, over the phone at a time most convenient to them). Members from outside the circle of care (research assistants) were responsible for conducting the informed consent process and interviews, to avoid undue influence on participants by their healthcare providers. Collecting additional demographics would be valuable in future studies to assess diversity of participants. Moreover, assessing hypothetical barriers and enablers may not always identify all possible issues. For instance, factors such as an individual's risk aversion may have a larger influence in actual decisions than in hypothetical decisions [
[49]
]. Though the interview study incorporated some elements that are suggested to have better consistency between hypothetical and actual decisions (e.g. questions frame participants as “the actor”; participants closely resemble those who will be making the actual decisions) [[49]
], assessing trial participants’ experiences through interviews or surveys throughout the trial may be valuable in determining additional barriers and enablers.Conclusions
By speaking with stakeholder groups before developing a clinical trial protocol, the authors have identified numerous modifiable factors related to information needs (e.g., concerns, misconceptions), preferences (e.g., information format, who to speak with about the trial) and resource needs to address potential barriers (e.g., additional staff and convenient appointments). By addressing and incorporating these findings into the clinical trial protocol, the authors hope to align trial processes with stakeholder needs and create a more patient- and physician-centered trial. In future studies the authors believe assessing barriers and enablers of trial implementation will be needed. Trial participants, patients who declined to participate, and select physicians involved in the care of trial participants could be interviewed. A process evaluation [
[50]
] that identifies barriers and enablers as the trial is being conducted would provide an in-depth understanding of delivery and receipt of the trial, address potential issues in a real-time manner, and even help inform next phase trial design.Funding
Support was provided by the Heart and Stroke Foundation of Canada (Bridge Grant) and a University of Ottawa Department of Anesthesiology and Pain Medicine Operating Grant. MML is supported by The Ottawa Hospital Anesthesia Alternate Funds Association and holds a University of Ottawa Junior Research Chair in innovative translational research. The funding sources had no involvement in the study design; collection, analysis and interpretation of data; writing of the article; or decision to submit the article for publication.
Author Contributions
Conception and design of the study: MF, DAF, GC, DIM, CDM, PJD, DJS, JP and MML. Acquisition of data: MF and AC. Analysis and interpretation of data: MF, VH, AC and JY. Drafting or revising the manuscript: MF, DAF, VH, AC, GC, JY, DIM, PJD, DJS, JP, CDM and MML. All authors have approved the final article.
Declaration of Competing Interest
The authors have no commercial, proprietary or financial interest in the products or companies described in this article.
Acknowledgments
The authors thank all patients and clinicians for volunteering their time to participate in this interview study. The authors also thank the patient partners for their contributions to this study.
Data and Materials Availability
All materials and datasets generated or analyzed during the current study are available from the correspondence author on reasonable request.
Appendix. Supplementary materials
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Article info
Publication history
Published online: April 06, 2022
Accepted:
August 25,
2021
Received:
June 2,
2021
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