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Justice and equity in pragmatic clinical trials: Considerations for pain research within integrated health systems

Abstract Introduction Pragmatic clinical trials (PCTs) can overcome implementation challenges for bringing evidence‐based therapies to people living with pain and co‐occurring conditions, providing actionable information for patients, providers, health systems, and policy makers. All studies, including those conducted within health systems that have a history of advancing equitable care, should make efforts to address justice and equity. Methods Drawing from collective experience within pragmatic pain clinical trials networks, and synthesizing relevant literature, our multidisciplinary working group examined challenges related to integrating justice and equity into pragmatic pain management research conducted in large, integrated health systems. Our analysis draws from military and veteran health system contexts but offers strategies to consider throughout the lifecycle of pragmatic research more widely. Results We found that PCTs present a unique opportunity to address major influences on health inequities by occupying a space between research, healthcare delivery, and the complexities of everyday life. We highlight key challenges that require attention to support complementary advancement of justice and equity via pragmatic research, offering several strategies that can be pursued. Conclusions Efforts are needed to engage diverse stakeholders broadly and creatively in PCTs, such as through dedicated health equity working groups and other collaborative relationships with stakeholders, to support robust and inclusive approaches to research design and implementation across study settings. These considerations, while essential to pain management research, offer important opportunities toward achieving more equitable healthcare and health systems to benefit people living with pain and co‐occurring conditions.

Conclusions: Efforts are needed to engage diverse stakeholders broadly and creatively in PCTs, such as through dedicated health equity working groups and other collaborative relationships with stakeholders, to support robust and inclusive approaches to research design and implementation across study settings. These considerations, while essential to pain management research, offer important opportunities toward achieving more equitable healthcare and health systems to benefit people living with pain and co-occurring conditions. pain is a persistent pain experience described variously, including pain intensity and interference with social and emotional functioning. 1 People with chronic pain often report multiple sites of pain and multiple co-occurring pain conditions, alongside other physical and mental health conditions. As such, chronic pain is often difficult to manage, and a growing conceptual and empirical literature supports models of integrated, multimodal pain care that incorporate a range of evidencebased interventions, including nonpharmacological treatments (NPTs). [2][3][4][5][6] Although many people experience chronic pain, certain populations are at greater risk, including severe, debilitating chronic pain. Military and veteran populations worldwide report particularly high rates of chronic pain and pain interference. [7][8][9] As such, pain management has become a priority for the U.S. Departments of Defense (DOD) and Veterans Affairs (VA), which have established an integrated stepped care model of pain management with clinical pathways that promote the use of NPTs, including complementary and integrative health approaches. 10 In one successful approach, for example, veterans with preexisting chronic pain and psychological comorbid conditions experienced decreases in pain and pain intensity after receiving auricular acupuncture, a protocolized NPT, in routine clinical settings. 11 Continued support for use of NPTs comes from evidence that active duty military service members with chronic pain who transitioned from DOD to care in VA facilities with prior exposure to NPTs were at significantly lower risk for new-onset alcohol and/or drug use disorder; poisoning with opioids, barbiturates, or sedatives; suicide ideation; and self-inflicted injuries including suicide attempts, compared to those who transitioned without prior exposure to NPTs. 12 Pragmatic approaches to research have recently gained traction for their ability to address urgent health care problems such as chronic pain, as well as to test the effectiveness and delivery of low-risk pain therapies to counter the nation's opioid epidemic. 13,14 These pragmatic clinical trials (PCTs) are designed to examine the effectiveness of interventions when embedded in healthcare systems with participants representing the population normally seen in clinical practice settings with a range of sociodemographic characteristics, variations of the condition being studied, and co-occurring conditions. 15 Whereas explanatory trials are designed to assess intervention efficacy in an ideal setting, pragmatic trials aim to test intervention effectiveness in a more generalizable setting. Compared to explanatory trial designs, PCTs have broader inclusion criteria and fewer exclusion criteria to allow for more flexible delivery of interventions. PCTs also tend to feature outcomes that are more acceptable and meaningful to participants, the ultimate beneficiaries of the research. These designs allow PCTs to be more likely to provide actionable information for patients, providers, and policy makers about how interventions work within complex care settings. 16 Yet, health systems are prone to disparities in healthcare access and quality that become exacerbated unless proactive steps are taken to address health equity, as has been articulated recently in the context of pragmatic research involving individuals with dementia. 17

| CONTEXTUALIZING INEQUITY AND INJUSTICE TO PAIN PCTs
In pragmatic research, inequity results from unfair distribution or realization of benefits and burdens of the research that stem from social conditions and/or structural characteristics of the healthcare systems where PCTs are conducted. Inequities can be described as a form of injustice, especially if they arise from the inadvertent neglect of a basic moral, legal, or human right-or from overt or systemic discrimination.
People with chronic pain may be vulnerable to experiences of injustice propagated by social factors including poverty, disability, poor social support, homelessness, isolation, and limited access to effective pain care. 5,18 These elements can carry over into the clinical research environment, which is a multidimensional system of influences that can accommodate, ignore, or exacerbate vulnerabilities. 19 Consonant with the biopsychosocial model of pain, which acknowledges its multiple components (biological, psychological, and social influences), these social factors can in turn negatively influence an individual's pain experience. 20 The dynamic interaction of factors within and across the biological, psychological, and social domains of pain therefore draws attention to vulnerabilities across all aspects of life.
It suggests that experiences under any one domain (eg, history of racial or sexual harassment and discrimination) can have broad biological, psychological, and social effects. Inequities arising from health systems and other sources can potentially amplify pre-existing individual vulnerabilities, interfere with the delivery of trial interventions, and delay pain recovery.
Ethical issues arising in PCTs include managing risk, informed consent, blurred distinctions between research and care, stakeholder representation, and collateral findings. [21][22][23][24][25][26][27][28][29][30] Because pragmatic research can be integrated deliberately within health systems already challenged by inequities, systematic consideration of the ethical dimensions of justice as applied to pain PCTs is also critical. Given the structural embeddedness of PCTs, the need arises in this context to focus attention on how the principle of justice-a cornerstone of the Belmont Report and other foundational research ethics guidelines-can be operationalized to address issues of structural injustice encountered during pragmatic research. 31 This can be facilitated through clear identification of the influences, roles, and responsibilities of all PCT stakeholders, including health providers, research sponsors, regulatory agencies, payers, institutional leadership, as well as advocacy and community organizations. 32,33 In many cases, these gatekeepers will need to be engaged actively to direct their influence towards documenting and rectifying inequities. Here we emphasize that there is an opportunity for pragmatic research itself to provide the knowledge necessary to facilitate this task.
Based on our experience with PCTs in health systems that serve military and veteran populations, 13

| CONSIDERING JUSTICE AND EQUITY ACROSS THE LIFE CYCLE OF PRAGMATIC RESEARCH
Comprehensive attention to justice not only has the potential to benefit people living with chronic pain, but also to strengthen the value, quality, and generalizability of pragmatic research. The several approaches described below to address equity within PCTs include targeted interventions at various stages of pragmatic research. Robust stakeholder engagement throughout the lifecycle of research, particularly involving people with lived experience that includes chronic pain and various psycho-social vulnerabilities, is essential to carry out these actions. Examples of these challenges and mitigation strategies are summarized in Table 1.

| Study context and design
Characteristics of people with chronic pain, of pain researchers, of systems for institutional oversight, and of the environment housing pragmatic research inevitably shape an individual participant's research experience. Funders often support PCT research in major academic health systems, because these systems offer access to relatively large numbers of patients and also tend to employ experienced research teams. However, large academic health systems may not represent environments where many individuals with chronic pain and co-occurring conditions, and who face existing health inequities, receive care. Incentivizing PCT partnerships between academic research institutions and less-resourced or underserved populations (eg, rural and those that serve a high percentage of patients from racial/ethnic minority groups) may support enhanced generalizability, utility, and equity of PCT findings.
A combination of factors-including those that are individual, collective, institutional, and structural-influence how data are collected, relevant outcomes are formulated, research-related behaviors are characterized, and findings are interpreted. [34][35][36] For example, as a structural matter, longstanding sociodemographic categories that are considered important factors in PCTs (eg, race/ethnicity based on administrative or clinical employee observation) 37 have been critiqued and could be supplemented with more current and nuanced patientreported measures of race, ethnicity, ability, or other characteristics. 38 Similarly, while PCTs strive for efficiency, sometimes by relying on electronic health records or patient portals for data collection, they may inadvertently bias their findings to settings that are wellresourced and comfortable with technology. They may also limit study measures and outcomes to those already integrated into particular systems, regardless of their alignment with the care needs and priorities of traditionally underserved populations. When designing and implementing PCTs, choices about where, when, and how to collect data should be carefully considered early and often, not only as a matter of trial integrity, but also to further goals of broad inclusion.  [42][43][44] In addition, between 15% and 40% of female veterans using VA services have experienced military sexual trauma. 45 Such trauma can contribute to the avoidance of care in an environment perceived as hostile, where many female T A B L E 1 Justice and equity-enhancing strategies for PCTs testing nonpharmacological treatments for chronic pain

Focal area
Examples of challenges Examples of mitigation strategies

Study context and design
• Potential for biases, prejudices, and inequities to transfer from health systems to PCTs.
• Understand, prospectively, community attitudes and beliefs regarding a health system and how these might transfer to aspects of trial implementation. • Develop, share, and enforce standards for equity and inclusion across the study team and supporting personnel. • Develop and employ innovative tools to prioritize equity on a routine basis across a health system (eg, electronic reminders about common health inequities that affect medical treatment).
• Limited accessibility to NPTs for some patients due to institutional biases and disincentives against NPTs. • Funding system that prioritizes health systems with strong academic partnerships, leading to the underrepresentation of less resourced health systems.
• Engage with institutional leadership prospectively to identify pathways for integration of pragmatism and NPTs. • Systematically review portfolios and funding strategies with an eye toward health system diversity, including bias education. • Specify and weight criteria that will be applied during grant review processes to achieve more equitable distribution of resources. • Incentivize partnerships between less-resourced health systems with academic research centers.
• Use of study outcome measures that do not necessarily align with what patients are most interested in, and sociodemographic categories that diverge from how participants view themselves.
• Engage patients/other stakeholders to identify meaningful study outcomes among specific populations. • If needed, supplement existing sociodemographic data with current patient-reported race/ethnicity/ability measures. • Create and include patient engagement groups as part of the research team and invite comments on choice and relevance of study outcomes.
• Limits on data collection and trial participation due to reliance on digital systems.
• Provide access to technology, through pragmatic means if feasible (eg, leverage existing technology support programs in healthcare systems). • Consider non-EHR based data collection for some populations Participant recruitment and retention • Limited participation of some individuals and groups due to diversity-insensitive recruitment approaches and materials.
• Identify potential barriers to trial participation prospectively, including through patient questionnaires designed for this purpose. • Create and include patient engagement groups as part of the research team who can review and offer feedback on recruitment methods and materials. • Include within recruitment materials culturally sensitive and specific images and language that include populations experiencing lower access to care or other known disparities within the study's health system.
• Limited participation of some individuals and groups by virtue of their transiency or difficulty accessing well-established health systems.
• Tailor recruitment to potentially excluded populations (eg, settings known to care for individuals who are transient or who commonly experience health disparities).

Study interventions
• Inflexible interventions that do not align with contextual needs or strong preference of patient populations.
• Identify multiple strategies (eg, individual and group-delivered interventions; condensed treatment schedules; multi-lingual therapy) to facilitate intervention delivery for different types of patient populations.

Stakeholder engagement
• Limited racial, ethnic, and ability diversity among providers, investigators, and study staff. • Inability to identify and respond to individual and structural barriers to trial participation by marginalized populations.
• Engage with diverse patient groups who can review and offer feedback on study design and implementation choices. • Invite patients who represent a study population formally to be members of the research team. • Offer structural competency and cultural sensitivity training for research and healthcare staff involved in PCTs. • Use known strategies to engage investigators from underrepresented groups (eg, diversity supplements; engage institutions that serve minority populations). • Encourage sharing of diverse perspectives within teams and actively counter microaggressions, rudeness, and harassment.
veterans have reported sexual harassment, 46 sexist treatment, and feeling like they do not belong. 47 As has been noted by othersincluding the VA Women's Health Practice-Based Research Network 48 -if these issues are not addressed directly as part of a trial's recruitment plan, there will remain a risk of systemic underrepresentation of women veterans in many embedded PCTs.
More broadly, PCTs can promote equitable inclusion by engaging patients with "real-life" co-occurring conditions that interact with the experience of pain, such as alcohol use disorder, who are routinely excluded from efficacy and even many effectiveness trials. 49  approach that has been used previously in military populations. [54][55][56] In another example of tailoring interventions to stakeholder needs, PCT researchers investigating mindfulness-based interventions for treating chronic pain collaborated with women veteran leaders who had prior exposure to mindfulness treatment to develop a facilitator-training module that addressed specific needs and experiences of female veterans. 57 In this work, all meditations were recorded with both male and female voices, and language in recruitment and course materials were carefully chosen to avoid being potentially disturbing to women. As these examples illustrate, there is a need for conscious and proactive engagement of stakeholders familiar with ability-and access-related challenges of patient beneficiaries of NPTs for managing chronic pain. groups-such as health equity advisory councils-with broad stakeholder representation are also useful to enhance engagement. 17   For more information about the NIH-DOD-VA Pain Management Collaboratory, visit https://painmanagementcollaboratory.org/.

CONFLICTS OF INTEREST
The authors declares no conflicts of interest.