Facilitators and Barriers to Spinal Cord Injury Clinical Trial Participation: Multi-National Perspective of People Living with Spinal Cord Injury

Introduction

The field of spinal cord injury (SCI) research is clearly advancing in its identification of potential therapeutics for translation into testing with clinical trials. These interventions include acute surgical decompression, neuroprotection, neural repair, cell replacement, activity-based rehabilitation, and medical devices, including devices requiring surgical implantation such as epidural stimulation and brain machine/computer interface. There are currently several phase I clinical trials ongoing, an increasing number of phase II trials are beginning, and there will be multiple phase II and III trials in the near future (see summary tables hosted on the Spinal Cord Outcomes Partnership Endeavor website regarding current SCI interventional clinical trials; www.scope-sci.org/trials.php). These trials will require large numbers of participants and will likely require multi-national collaborations. By nature, clinical trials can have strict inclusion and exclusion criteria, which narrow down the pool of potential participants. Meeting enrollment numbers for properly powered trials is a daunting yet critical task. Therefore, it is important that the field design these trials in a manner that facilitates participation.

Recruitment and enrollment for clinical trial participation can be impacted by many factors, as highlighted throughout the literature across diseases. Some of these factors may be less amenable to change due to the research question, such as inclusion/exclusion criteria, and other factors may be dependent upon financial resources, such as the number of trial sites that can be funded. However, once appropriately qualified individuals are identified, there is no guarantee that they will decide to participate in a trial. There has been some study of factors that influence the choice to participate from the perspective of individuals living with cancer, the older adult population, and individuals living with sickle cell anemia ^{1 –4} . In cancer, for example, barriers to participation that have been identified by potential participants include the understanding of randomization, assignment to placebo or treatment, possible adverse effects, unease with research, complex protocols, financial burden, transportation logistics, and trust in physicians. ¹ In the older adult population, for example, barriers to participation in interventional trials include understanding complex documents (e.g., overly complex consent forms), distrust of research, transportation, lack of understanding of the study protocol, concern about excessive intrusiveness, and family members acting as gatekeepers/proxies. ^2,3 In sickle cell anemia, barriers to participation include general mistrust of research, emotional and practical concerns, the possibility of randomization, and unknown long-term risks; facilitators include more education—specifically, peer education and improved education in study rationale. ⁴ In the current study, we chose barriers to be evaluated that are common across the three populations for which there is literature to determine if they are common in the SCI population, as well.

To design clinical trials targeting SCI in a manner that facilitates participation, it is important to obtain information from the perspective of potential participants (i.e., people living with SCI). One method of obtaining information from large numbers of people is to do a survey. The Internet has become a useful tool by which to conduct research. ¹³ Online research methods have many potential benefits, including the possibility of increasing the geographical span, as well as inclusion of individuals with mobility or communication difficulties. ¹³ Previous studies show that people with SCI prefer to receive research information over the Internet ⁵ and important scientific information can be gained from Internet-based research survey to guide research priorities. ^{6 –9}

A survey was developed targeting a multi-national population of individuals living with SCI to determine whether a host of factors, drawn from the literature, were viewed as facilitators or barriers to making a decision to participate in an interventional clinical trial.

Methods

Results

Factors that are universally facilitators, barriers, or neutral

As described in the Methods section, a factor was considered to be universal if at least 50% of the respondents in at least 15 of the 17 sub-groups analyzed rated it as a facilitator, barrier, or neutral (for a full reporting of results for all 17 sub-groups analyzed, see Supplementary Table 1; see online supplementary material at www.liebertpub.com). There were 13 factors that fit the criteria of being rated as a universal facilitator (Fig. 1A). The highest rated facilitators were possible improvement in functionality (91%), better understanding of your SCI (86%), opportunity to help future people with SCI even if you do not experience improvement (altruism, 85%), access to cutting edge care (85%), opportunity to learn more about your health (85%), wish to be more independent (83%), and opportunity to receive free (extra) medical tests or treatment (77%). There were six other universal facilitators that were rated between 50–80% (Fig. 1). There were five factors that were rated as universal barriers to clinical trial participation (Fig. 1B). The highest rated barriers were possible decline in functionality (80%), possible side effects (70%), and possible out-of-pocket expenses (64%). There were only three factors that met the criteria of being universally neutral (Fig. 1C); these were religious issues (71%), prior experience with clinical trials (66%), and privacy issues (63%).

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FIG. 1.

Universal factors. (A) Factors that were rated as universal facilitators by at least 15 of the 17 subgroups analyzed. (B) Factors that were rated as universally neutral by at least 15 of the 17 subgroups analyzed. (C) Factors that were rated as universal barriers by at least 15 of the 17 subgroups analyzed. Color image is available online at www.liebertpub.com/neu

Factors that were divided

The remaining 11 factors evoked divided responses that overall were not strong facilitators or barriers (Fig. 2). One of the divided factors, knowledge about clinical trials, trended towards being a facilitator, with 89% of respondents considering it to be neutral or a facilitator. Figure 3 shows the variety of responses regarding these 11 factors from the 17 subgroups analyzed. More than 50% of the Latin America and Caribbean, Oceania, and Asian subgroups rated this as a facilitator (Fig. 1A). Five other factors trended towards being barriers (Fig. 3A). Transportation to/from the research facility (Fig. 3A) was a clear barrier for the Asian and Canadian subgroups, the 11-20 and >20 years post-injury subgroups, the 46–60 years age subgroup, and the female subgroup. Family obligations (Fig. 3A) was rated as a barrier by 52% of the Latin America and Caribbean subgroup. The final five factors had no clear trend towards being either a facilitator or a barrier (Fig. 3B). Interestingly, all 17 subgroups were near equally divided on how they rated being a “guinea pig” (Fig. 3B) and possibility of being in the “control group” (Fig. 3B). Possible impact on caregiver/attendant/assistant was close to being scored as universally neutral, with 14 of 17 subgroups viewing it as neutral (Fig. 3B).

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FIG. 2.

Factors that yielded divided responses. Color image is available online at www.liebertpub.com/neu

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FIG. 3.

Divided factors. (A) Factors that were divided in response, but demonstrated a majority trend towards being either neutral or a facilitator (3A.1) or neutral or a barrier (3A.2-6). (B) Factors that were divided with no clear trends. For all, rows are factors, columns are participant subgroups. In each row, blue indicates the percentage of the subgroup who rated the factor a facilitator (+1 to +3); beige indicates the percentage who rated the factor neutral (0); red indicates the percentage of the subgroup who rated the factor a barrier (−1 to −3). For any subgroup where there was a majority perception, we identified that by overlaying it with the actual percentage. Color image is available online at www.liebertpub.com/neu

Discussion

A multi-national survey was conducted in which a large sample of individuals living with SCI, primarily chronic injury, ranked 32 factors as facilitators or barriers to their decision making process regarding participation in interventional clinical trials. There were 13 universal facilitators, five universal barriers, and three universally neutral factors.

Some of the high ranking universal facilitators were factors that one would intuitively think would be important when making a decision about clinical trial participation, such as the possible improvement in functionality and the wish to be more independent, which are both related to the ultimate goal of the intervention being efficacious. However, when efficacy is unknown, for example with Phase I trials, or when a control group is required, for example in Phase II and III trials, there are other unexpected factors that can strongly facilitate participation. These include the opportunity to learn more about your general health and to better understand your SCI, recommendation from SCI peers, and the simple desire to participate in something that maintains hope. These are factors that could easily be taken into consideration during the design of trials by creating educational feedback opportunities to participants, as well as engaging other individuals living with SCI to be team members.

Similarly, some of the universal barriers were factors to be expected, such as the possibility of adverse effects and possible decline in function, which are strongly considered when weighing the risk versus benefit probabilities of translating an intervention. However, many barriers were identified that are not related to physical/medical risks—specifically, the possibility of out-of-pocket expenses, concern about losing medical coverage, and concern about losing income. It is true that research procedures in a clinical trial are not charged to the participant. However, if travel is required and not paid for by the research team, it is an out-of-pocket expense; if an attendant is needed to assist with completion of certain tasks for the trial and the cost is not paid for by the research team, it is an out-of-pocket expense. Medical coverage or disability income is often tied to certain definitions of disability (for the U.S., see the Social Security Advisory Board definition of disability. There is a legitimate fear that participating in a clinical trial could improve function enough to disqualify the person from maintaining their medical coverage or disability income, yet not improve function to the degree that those supplements are no longer needed. Similarly, a concern for those individuals who are already working and bringing in a steady income is that the time commitment of participating in a clinical trial may be so onerous that it may negatively impact their work and cause them to lose essential income. All of these factors should be taken into careful and active consideration when designing clinical trials so as to promote enrollment, reduce participant burden, and enable adherence to different protocols.

There also were certain factors that were stronger barriers or facilitators for certain sub-groups of people living with SCI (Fig. 3). There may be a need to tailor design based on “geographic” region, taking into account sociocultural sensitivities. For example, survey participants in Latin America and the Caribbean rated family obligations and possible impact on family/friends as barriers. It would be important to understand more about these concerns, for example, do individuals with SCI living in these countries rely more heavily on family and friends for their care and income? If so, then it would be critically important to design protocols that do not overly burden the family. Transportation to/from the research facility was a barrier for multiple sub-groups (see Fig. 3A). This can be addressed in multiple ways in protocol design, for example reimbursing transportation costs, providing actual transportation, reducing the number of visits to the research facility, and/or using more telemonitoring. Minimizing the time commitment also can reduce the impact on work and family obligations, thus reducing multiple barriers.

Ultimately, when designing clinical trial protocols, a balance has to be made between obtaining the most data possible and actually being able to complete the trial. If a trial is designed in a manner that generates too many barriers, people either will not participate or they will enroll and then drop out—neither of which enables translation. The data presented here have identified multiple barriers that can be removed or lessened and multiple facilitators that can be enhanced in relatively easy ways. One has to be careful, however, that facilitators are not used to the extent that they become coercive. In the end, there is still risk of functional loss and adverse effects when testing experimental interventions and potential participants need to be made aware of the risks that may be involved.

Consumer engagement has been largely untapped in the SCI clinical trial realm. In the cancer literature, there is a strong push for participant advocates, peer mentors, and participant navigators to enhance clinical trial recruitment and retention. ¹ The survey results presented here demonstrate that recommendations from SCI peers is a very strong facilitator. Additionally, approaches used in community-based participatory research are recommended by the cancer field, as well, such as the inclusion of community stakeholders in trial design. ¹ Results from the current survey can be used as a first step in engaging SCI consumers in protocol design. Community physicians (e.g., physicians who care for people living with SCI who do not have expertise in SCI medicine, or physicians who are not associated with academic medical centers) are also stakeholders who should be engaged. ¹ They can be valuable sources of referral to clinical trial investigators and, based on the data presented here, they can facilitate the decision of individuals with SCI to participate (see Fig. 1B). This also could also be a barrier, however, if community physicians are unaware of clinical trials for SCI or have a negative viewpoint. Improved education or awareness of this referral source could be an activity taken on by SCI professional organizations.

A recent systematic review of the literature demonstrates that participant engagement in various types of health care research is highly feasible, can be conducted in many different settings, and via a variety of methods. ¹² It has been shown to increase enrollment, help secure funding (note the new and growing Patient Centered Outcomes Research Institute funded by the U.S. government, which is heavily focused on engagement), aid in study design, and of particular importance to help improve the choice of relevant outcome measures. There can be challenges, of course—the most commonly cited ones being the extra time and funding needed for engagement and the worry that “engagement” reflects a token commitment. ¹²

Conclusion

The value of creating a mutually respected partnership between SCI consumers and researchers to better inform and enable successful clinical trials is well worth any challenges that may need to be overcome. The data presented here provide one avenue by which we can begin to think about changing small but significant aspects in clinical trial design that could have an amplified effect on trial success.