“I’m tired of seeing my friends die”: barriers and facilitators to participating in clinical trials among rural people who use drugs in the United States

Abstract

Purpose:

Participation in clinical trials among people who use drugs (PWUD) in rural areas remains disproportionately low compared to those in urban communities. Our objective was to describe barriers and facilitators to clinical trial participation among this understudied and underserved population.

Methods:

We conducted semi-structured in-depth interviews among rural PWUD in Kentucky, Ohio, and Oregon. Using the Ickovics and Meisler framework, we classified factors associated with participation in clinical trials among rural PWUD into five categories: the individual, trial and intervention characteristics, participant-trial staff relationship, clinical trial setting, and features of the disease. We used inductive qualitative analysis methods to identify salient themes.

Findings:

Thirty-five rural participants (median age: 39, 51% men) completed in-depth interviews. Facilitators for rural clinical trial participation were mainly situated within the individual, trial and intervention characteristics, and clinical trial setting. Individual characteristics such as altruistic motivations to help their communities and peers and trial and intervention characteristics like visit reminders and resource assistance were the most frequently noted facilitators of clinical trial participation. In contrast, participation barriers were mainly related to participant-trial staff relationships and disease features. Judgmental and untrustworthy trial staff and involvement with the criminal legal system were obstacles to clinical trial participation.

Conclusions:

Individual, intrapersonal, and logistical factors described by rural PWUD must be addressed to enhance the participation and retention of this population in clinical trials. Successful clinical trial participation may contribute to equitable access to essential health services by PWUD in rural communities.

Introduction

In the United States, substance use disorders (SUD) and related harms, such as overdose deaths and associated infections, have increased over the past two decades.^1–3 The substance use epidemic and its consequences have greatly burdened many rural communities.^4–6 Methamphetamine, prescription opioids, heroin, and fentanyl use in rural communities is due to increased availability and marketing, economic hardship caused by out-migration and high unemployment rates, and tight-knit communities that can facilitate access to opioids from friends and family.^{5, 7} Despite rising overdose deaths in many rural communities,^8–10 screening and treatment for SUD and their associated infections remain insufficient.^11–16 People who use drugs (PWUD) in rural communities have limited access to treatment due to long travel distances and waiting lists, limited opioid treatment programs, and concerns about a lack of trained providers.^{4, 17–21} When SUD are left untreated, PWUD are at increased risk of overdose,²² HIV and HCV infections,^{23, 24} mental health disorders,^{25, 26} and cardiovascular disease.²⁷

Clinical trials for substance use treatment and prevention and associated conditions such as HIV and HCV are underway, with strong potential for shifting these national crises. However, the inclusion of rural PWUD is critical for translating the results of these trials to rural communities. PWUD, particularly within rural settings, are largely underrepresented within clinical trials.^28–31 Clinical trials often recruit from research centers urban areas with supportive infrastructure, such as public transportation and large clinical environments. Results from these trials may not translate to rural settings, where communities may differ greatly demographically, socioculturally, and structurally. PWUD from rural settings must be more fully engaged in clinical trials for equitable success and translation of emerging novel modalities addressing these epidemics.

Engaging PWUD within sparsely populated US rural communities will require a better understanding of these distinct settings’ sociocultural context and operational issues. Perceived stigma, scheduling and transportation difficulties, community distrust of research, unaddressed withdrawal symptoms, lack of preparation for coping with real-world triggers for substance use, and limited cultural competence are known barriers to participation in available evidence-based treatment,^{19, 20} and likely also influence clinical trial participation.³² In contrast, social support and self-efficacy are known facilitators of participation and retention.³³ Some rural PWUD report considering the amount of financial compensation, the confidentiality of their information, whether free healthcare services are included in the trial, and their altruistic motivations when deciding to participate in and remain in studies.^{32, 34, 35} Perceived barriers to remaining in a clinical study include frequent contact information changes which render study staff unable to schedule and confirm follow-up appointments and issues securing transportation.³²

We conducted a qualitative study among PWUD from rural Kentucky, Ohio, and Oregon communities. We used and adapted the Ickovics and Meisler³⁶ framework of recruitment, adherence, and retention in AIDS clinical trials to identify the barriers and facilitators to clinical trial participation for PWUD in rural settings.

Methods

Study Design

We conducted in-depth, qualitative interviews to understand the barriers and facilitators to clinical trial participation among people who use drugs (n=35) recruited from rural, western Oregon and rural Appalachian Ohio and Kentucky. The data collected informed the development of training content to evaluate the effectiveness of a peer-driven retention intervention, the Peer-Based Retention Of People Who Use Drugs In Rural Research (PROUD-R²), described in detail elsewhere.³⁷

Sampling and Recruitment

The population of interest for this study were people who have recently injected drugs or used opioids through any route of administration to get high in the past 30 days in rural Oregon, Appalachian Kentucky, and Ohio, and were age 18 or older. Recruitment for the interviews leveraged the infrastructure of the National Rural Opioid Initiative (NROI) cohort studies that were ongoing in the study areas.³⁸ NROI sites were defined as rural based on the funding agencies assessment using the “Am I Rural” website (https://www.ruralhealthinfo.org/am-i-rural) from the US Health Resources and Services Administration.³⁸ NROI participants were recruited using a harmonized respondent-driven sampling approach³⁹ and community outreach at locations such as syringe services programs and community health centers. Participants who enrolled in the NROI studies after April 2019 were screened and invited to participate in the PROUD-R² study. Purposive recruitment ensured a balanced representation across the three sites and between genders. There were no exclusion criteria.

Data Collection

Once the participant provided informed consent, they completed semi-structured in-depth interviews. Interview guide topics included: demographics, drug use and clinical care, perceptions of clinical trial research, motivations for clinical trial participation, and preferences for clinical trial retention. Before participants were asked about their perception of clinical trials, they were provided with the following definition adapted from the National Institute on Aging,⁴⁰ “A clinical trial is a type of research that tests treatments and medications. People agree to participate voluntarily and may receive specific medicines, shots, or treatments during the research. The goal for clinical trials is to add to medical knowledge and improve people’s health.” Staff members with training and experience in qualitative methods conducted all interviews in a location that assured participant privacy and confidentiality. All interviews lasted approximately 60 minutes and were audio recorded. Once the interviews concluded, participants completed a short survey on demographic characteristics.

Data Analysis

Audio recordings were transcribed, coded, and analyzed using Dedoose qualitative analysis software. Study staff transcribed the interviews. Electronic recordings and transcription files were transferred using secure methods, and all participant identifiers were removed from transcripts. We conducted an inductive, thematic qualitative data analysis of the transcribed audio recordings. Transcripts from all three study sites were randomly assigned to a coder. Then, two coders independently coded the transcripts assigned to them. Coders also left memos on transcripts. The primary purpose of memo-ing was to communicate with the other coders and deepen analysis as new themes and patterns emerged in the transcript. A third coder reviewed the coding done by both people. All three coders met on a bi-weekly basis to discuss any discrepancies. If needed, they also adjusted the codebook during this time. We initially developed the codebook using the survey questions derived from the Ickovics and Meisler framework and updated it as we moved through the coding process. After coding was complete, a combination of charts and lists organized the coded excerpts systematically. Once all the data was organized, we looked at peoples’ facilitators and barriers to clinical trial enrollment and retention.

Ethics

Prior to data collection, research staff obtained informed consent from participants. All audio files were saved on a password-protected, access-limited server, and any physical copies of the files were kept in a locked, limited-access storage location.

Results

Sample characteristics

Thirty-five participants completed in-depth interviews in Kentucky, Ohio, and Oregon (Table 1). The sample included an equal distribution of men and women, and the median age of participants was 39 years.

Table 1.

Characteristics of rural people who use drugs who participated in qualitative interviews on clinical research participation and retention, 2019

	Total		Kentucky		Ohio		Oregon
	n	%	n	%	n	%	n	%
	35	100%	10	28.5%	10	28.5%	15	43%
Age, median (IQR)	39	(31, 46)	34	(30, 43)	43	(39, 54)	36	(30, 46)
Gender
Woman	17	49%	5	50%	5	50%	7	47%
Man	18	51%	5	50%	5	50%	8	53%

Qualitative findings

We described identified barriers and facilitators to clinical trial participation and retention using and adapting the Ickovics and Meisler framework of recruitment, adherence, and retention in AIDS clinical trials. Predominant themes of clinical trial participation and retention emerged and aligned with the Ickovics and Meisler framework: individual characteristics, trial and intervention characteristics, participant-research staff relationship, clinical trial setting, and features of the disease. Figure 1 illustrates our findings and adaptation of the Ickovics and Meisler framework to focus on factors that influence participation and retention among PWUD in clinical trials. Our qualitative analysis also explored differences by site and participant demographics.

Figure 1.

Conceptual framework of factors associated with clinical trial participation among rural people who use drugs in Kentucky, Ohio, and Oregon, 2019

Individual Characteristics

Perceived facilitators to clinical trial participation included the perceived treatment efficacy, gained sense of belonging, and altruistic motivations to help their communities and peers. Concern for privacy and confidentiality served as perceived barriers to clinical trial participation.

Most participants believed participating in a substance use-related clinical trial would facilitate a better quality of life, with an ultimate personal goal of eliminating substance use and maintaining recovery. Many expressed that regardless of the likelihood of treatment efficacy, the possibility of a trial treatment to “work” was enough to participate.

“Because I was never okay with being a drug addict or I was never okay with being stuck on meth it felt like. And so, I wouldn’t care if it even worked, just the thought of having something to try, to be a better mom, be a better wife, it was worth it for me”. (22, Female, Kentucky)

However, some participants discussed a strong desire to participate in a clinical trial with a primary objective to “cure” their SUD.

“[To participate] I would like to know what the end result would be ... Like this I know is a cure, that’s what the end result is … [I would not participate if it] wouldn’t be worthwhile. An endless thing, I’m somebody that would like to see results. I wouldn’t want to participate in something that’s going to last for ten years at my age.” (59, Male, Ohio)

Participants, particularly in Kentucky and Ohio, also discussed the benefits of belonging and the opportunity to gain knowledge about resource availability in the community. While participants acknowledged that they hoped to maintain their privacy around substance use, they expressed a motivation to participate in clinical trials as a way to feel connected with other PWUD who may have shared experiences, even if they are not directly interacting with them. Furthermore, participants expressed a desire to learn about available resources or education related to substance use through their participation.

“…anything that helps and tell other people about might help them too… [and to] just learn stuff. And help friends that too—I had a bunch of friends overdose and stuff like that …” (32, Male, Kentucky)

Altruistic motivations to help their communities and substance-using peers motivated some participants to participate. According to participants, mainly women, concerns about the next generation and helping other PWUD were motivating altruistic benefits. After reflecting on the trauma of losing a loved one, participants perceived helping others through a clinical trial indirectly limits emotional trauma by avoiding future traumatic losses. Participants reflected on the challenges of living with a substance use disorder; a trial with an intervention that could help ease the hardship of PWUD is worth attempting and participating in.

“Hopefully, it’ll help get more in the community so not only I can get clean, but hopefully everybody else does too. I’m tired of seeing my friends die.” (39, Female, Ohio)

Several participants weighed perceived risks and benefits. Participants recognized that clinical trial participation may require sharing personal information, such as contact information, to staff who are likely members of their community, and that there was a possibility of unintended disclosure of substance use to community members (i.e., if someone knew they participated in a substance use clinical trial, one could presume they were using substances). However, these concerns were weighed against the possibility of participating in a clinical trial that may provide treatment or eliminate their SUD. Overall, most participants believed the benefits of a clinical trial would outweigh the risks.

Trial and Intervention Characteristics

Participants described a strong desire to participate in a trial where they experience the efficacy of an intervention and have a clear understanding of the trial objective to facilitate participation. Additionally, some participants voiced concerns about safety, negative side effects, and lack of improvement or health benefits in the clinical trial. Some felt that they and other PWUD would be more motivated to participate in clinical trials if they were aware of the goal of the study and how the study was progressing.

“You want some feedback, what it’s actually doing, you know, how many people it’s actually helping, you know” (43, Male, Kentucky)

Others mentioned not wanting to participate or being the first to participate because of possible safety risks. One participant clearly expressed wanting to know “A hundred percent for certain that [the intervention is] not going to kill nobody. Or hurt them” (43, Male, Kentucky). However, most participants had few safety concerns.

Participant-Research Staff Relationship

Participant-research staff relationship factors were discussed as both facilitators and barriers to clinical trial participation. Specifically, participants described that non-judgmental clinical trial staff were essential to engage them in clinical trials. They openly discussed needing to trust staff to help maintain their privacy and confidentiality.

Participants want to feel like the trial staff are there to support and not judge them. Many expressed needing to feel comfortable with everyone they interacted with in the clinical trial activities. Participants desired to be treated well and in a friendly manner for clinical staff gain their trust.

However, judgmental attitudes of trial staff could negatively affect clinical trial participation. A few participants described situations where they felt judged in other daily settings which resulted in participants avoiding future interactions. They also stated that they would likely stop participating in a clinical trial if they were treated similarly.

“Non-judgmental staff was probably the big one for me I know because if I feel like I am being looking down, it’s like, nah, I’m good” (32, Female, Oregon)

Participants also noted that clinical trial participation could involve disclosing personal, traumatic, and often illegal activities, and therefore, maintaining confidentiality was critical.

“… I don’t have confidence in the people that I am working with and-- I am already really uncomfortable even talking about this stuff with you, you are a complete stranger and it’s-- these are like deep, deep, personal issues that you know, we are afflicted with an[d] so forth.” (30, Male, Oregon)

One reason participants feel comfortable engaging in current research studies is the privacy and confidentiality of trial staff. Participants conveyed the importance of privacy across all sites, but mainly in Ohio and Kentucky.

“…I don’t think they [research staff] can do anything wrong with me. I like them all. You know, because they’re all private and don’t say nothing, nobody or anything. They just seclude privacy, you know. And that means a lot.” (43, Male, Kentucky)

Clinical Trial Setting

Overall, participants commonly discussed needing clinical trial study visit reminders and considerations for study visit locations and frequency. Additionally, transportation was a commonly identified need for clinical trial participation. Broader financial and resource assistance to provide for basic needs, such as food or housing, was also commonly discussed among participants at all sites.

Study visit reminders was the most commonly expressed necessary facilitator to clinical trial participation. Participants mentioned different helpful reminder modalities. One of the more common approaches was text reminders that would include the location and time of the visit. Generally, participants felt a text message appointment a week prior would be sufficient. A few participants also mentioned having physical visit reminders, such as an appointment card. This way, participants will have a tangible reminder. One participant mentioned pinning reminders to the refrigerator to keep them organized.

“On my refrigerator, what I do daily, today, I got to do this, this, and this. And I kinda stick to it, unless something sidetracks me, but I’ll always go back and make sure that it’s there, what I had to do.” (54, Male, Ohio)

Participants also noted location, frequency, and time of study visits are important to maintain participation. Location is important in determining the number of times the participant is willing to travel to an appointment. If the appointment location is far, participants are likelier to attend appointments less frequently. Participants acknowledged that their preferred location would be in town or near town business districts to ensure they could travel to the appointment and would be more enticed to attend it. If the appointment was out of town, most would be unable to participate. It was also recommended that study visits should be held at a private location to avoid embarrassment or disclosure of substance use.

“Might be embarrassed thinking somebody’s watching them. A lot of them out there do think that looking to see if a co-worker, or a friend. That they don’t want to know or see him go in like, if they’re going to school. If a teenager’s going to school, they’re not going to want one of her friends see them come in.” (54, Male, Ohio)

Regarding appointment scheduling, a few participants had conflicts due to work and other responsibilities. Optimal times for scheduling trial study visits, such as mornings, weekends, etc., did not emerge as participants had unique time constraints.

Transportation was commonly noted across all sites as a barrier to clinical trial participation. Most participants discussed having to rely on family and friends to take them to various appointments or possibly clinical trial study visits, and their transportation was often unreliable.

“Pretty much just transportation is my only downfall right now.…you don’t even know how hard it is to get any family, friends, to go to appointments that you desperately need to go to…And people will say, they’ll show and come and get you, and then they won’t, you know.” (Female, 48, Kentucky)

Participants mentioned several approaches for facilitating transportation. Some participants had been part of other research studies where transportation was provided. Also, a transportation service coordinated through the clinical trial could facilitate retention.

Further financial and resource assistance for their time was a facilitator for clinical trial participation. Participants noted that receiving compensation for time and travel would facilitate their participation in a clinical trial. Specifically, the cost of gas was noted as a barrier, and support to offset travel costs would be necessary, and a few participants suggested gas station gift cards. Also, participants spoke about the importance of receiving cash as participation compensation as it could support purchasing food or housing needs, and not purchasing drugs. Beyond cash, participants discussed additional resource assistance, such as free meals or housing assistance with participation.

Specifically for women, if childcare is not provided as part of participation, they are more likely to not attend, and therefore, fail to continue in the study.

“If they had the adequate childcare provided for them, you know, or a daycare center, while they’re in there doing the clinical studies, have a daycare where they can keep their kids there too, you know, so…Trust me there’s a lot of people here that has got a lot of kids”. (43, Male, Kentucky)

Features of the Disease

Participants at all sites discussed the participation challenges related to SUD, including disease management and criminal legal system involvement. Some participants mentioned concerns about missing clinical trial study visits because of heavy substance use or being ill from withdrawal. Specifically, if experiencing withdrawal symptoms, the likelihood of skipping study visits increases, and trial staff may not be informed ahead of time. Many participants also spoke to needing flexibility for trial participation as their involvement could conflict with ongoing doctor’s appointments for SUD or related conditions, such as HCV, and in-patient or residential treatment needs.

“Yeah, keep your hours flexible, you know. To fit people schedules, looking at an eighteen hour window everyday that you want to have open to get your information because otherwise you ain’t going to get them back, you are going to have a lot of loss.” (46, Male, Oregon)

At all sites, participants noted that interactions with the criminal legal system occur more often among PWUD. These interactions emerged as barriers to clinical trial participation in several ways. Some spoke to the inability to drive because their license was taken away. Others feared that law enforcement would be connected or be able to use identifiable information from a clinical trial.

“[If researchers] tell me my stuff wasn’t confidential that’d probably be the only way I wouldn’t come. If me and you, I was talking to you and you went and said that I said this and I had a warrant and went and told, you know what I mean, where I was at or where my location is, yeah I wouldn’t come back.” (29, Male, Kentucky)

Discussion

Our study highlights the significant barriers and facilitators to clinical trial participation among PWUD in rural settings, specifically in Kentucky, Ohio, and Oregon. The findings underscore the importance of considering rural communities’ unique sociocultural and operational contexts to enhance the efficacy of clinical trials targeting SUD and related harms (Figure 2). By focusing on the perspectives of PWUD, the study highlights the critical importance of incorporating end-user insights into the design and implementation of clinical trials. This participant-centered approach ensures that our findings are directly relevant to improving trial participation and retention among this population.

Figure 2.

Recommendations for rural clinical trial designs to enroll and retain PWUD

Individual characteristics, especially altruistic motivations, played a substantial role in influencing participation decisions. Participants cited perceived treatment efficacy, a sense of belonging, and altruistic motivations as primary facilitators. Many participants expressed a willingness to participate in trials to improve their own health and support their recovery journey. This finding aligns with the broader literature, which suggests that personal health benefits and altruism are significant motivators for clinical trial participation.^41–44 Previously, “conditional altruism” was described as a willingness to help others and as an initial motivation to participate in a trial. However, participation may be more dependent on personal benefit from the trial.⁴⁴ The difference between motivation and participation should be further examined. Concerns about privacy and confidentiality emerged as substantial barriers, particularly in tight-knit rural communities with high risks of stigma. Ensuring robust privacy measures and clear communication about confidentiality can mitigate these concerns and enhance participation rates.

Participants emphasized the importance of understanding the trial’s objectives and experiencing tangible health benefits as critical factors influencing their participation. This highlights the need for transparent communication about the trial’s goals, potential risks, and benefits, corroborated by existing evidence. In prior trials, participants were more likely to enroll when they clearly understood the study’s purpose and potential trial outcomes.⁴⁵ Additionally, addressing these concerns through detailed, ongoing communication can build trust and enhance the perceived value of participating in clinical trials.⁴⁶ Decision aids for PWUD may help facilitate informed and voluntary consent.^{47, 48} These aids can clarify complex information, ensuring that participants fully comprehend the implications of their involvement, which can further enhance the perceived value of participating in clinical trials.

The relationship between participants and research staff is pivotal in fostering trust and encouraging trial participation, particularly given the rural context. Research has shown that when research staff are trained in cultural competence and empathetic communication, they are better equipped to create a supportive environment that resonates with participants’ unique backgrounds and needs.⁴⁹ Additionally, maintaining strict confidentiality and showing respect for participants’ experiences and challenges are critical factors in strengthening the relationship between participants and research staff.^{50, 51} This is particularly important in rural areas, where the close-knit nature of communities can exacerbate privacy concerns, further complicating the recruitment and retention process.⁵²

Clinical trial settings and logistical considerations will likely be critical for maintaining participation and overcoming commonly identified barriers to accessing care. Participants indicated that text reminders, accessible locations, and reliable transportation services are vital facilitators. Technology, including the use of text message reminders, has been effective in enhancing trial participation and retention.^{50, 53, 54} Financial compensation and resource assistance, such as gas cards or meal vouchers, can further incentivize participation and mitigate economic barriers.⁵¹ Future trials could explore the integration of more advanced features, such as real-time location tracking for transportation services or virtual trial components to reduce the need for physical attendance. Evaluating the impact of different types and amounts of financial compensation and resource assistance on trial participation rates for PWUD in rural settings. This might include experimenting with various incentive structures, such as tiered compensation or the provision of additional resources like childcare or internet access for virtual trial participation.^{55, 56}

The chronic and often chaotic nature of SUD, coupled with legal system involvement, presents unique challenges for trial participation. Participants frequently mentioned the need for flexibility in scheduling study visits due to health fluctuations and legal constraints. Providing flexible scheduling options and accommodating participants’ medical and legal appointments can enhance retention. Addressing the fear of legal repercussions by ensuring strict confidentiality can alleviate concerns and encourage participation.

While in-depth interviews provide rich, contextualized data, the small sample size and focus on specific rural regions (Kentucky, Ohio, and Oregon) may not fully capture the diverse experiences of PWUD in other rural settings across the United States. However, the use of in-depth qualitative interviews allowed for a comprehensive exploration of the nuanced barriers and facilitators to clinical trial participation from the perspective of rural PWUD and offered a deeper understanding of participants’ lived experiences. Logistical constraints limited our ability to conduct interviews in all potentially relevant rural areas, and the study was conducted before the COVID-19 pandemic. The pandemic has likely altered the landscape of substance use and service provision in rural areas, meaning that some of our findings might not entirely reflect current circumstances. Nonetheless, adapting the Ickovics and Meisler framework for recruitment, adherence, and retention in AIDS clinical trials provided a structured data analysis approach. This theoretical grounding ensures that our findings are systematically organized and relevant to existing evidence on clinical trial participation across diverse populations of rural PWUD.

Conclusions

Our study elucidates the complex interplay of individual, relational, and logistical factors that influence clinical trial participation among rural PWUD. By incorporating end-user insights into the design and implementation of clinical trials, researchers can develop more effective, culturally sensitive, and contextually relevant interventions. Emphasizing privacy, providing clear communication, ensuring supportive interactions with trial staff, and addressing practical barriers are critical steps toward enhancing the participation and retention of rural PWUD in clinical trials. These strategies improve the feasibility and success of clinical trials and contribute to equitable access to essential health services and the overall well-being of PWUD in rural communities.