Pain Management Collaboratory Research Articles

Adapting to change: experiences and recommendations from the Pain Management Collaboratory on modifying statistical analysis plans.

Best practices for clinical trials stipulate that statistical analysis plans (SAPs) need to be finalized before initiation of any analysis. However, there is limited guidance about when changes to SAPs are acceptable and how these changes should be incorporated into the research plan with appropriate documentation. We conducted a survey of 12 pragmatic clinical trials (PCTs) in the Pain Management Collaboratory that evaluated nonpharmacological interventions for pain to assess the following SAP information: (1) location of statistical analysis details, (2) types of statistical analyses planned, (3) sponsor requirements, (4) templates used for development, (5) publication plan, (6) changes since trial launch, (7) process of documenting changes, and (8) process of updating the trial registry. All 12 PCTs provided details of their SAPs for the primary outcomes in the institutional review board-approved trial protocol; 8 included plans for secondary outcomes, and 6 included plans for tertiary/exploratory outcomes. Most PCTs made SAP changes after trial initiation, many as a result of COVID-19-related issues. Eleven of the PCTs were actively recruiting participants. Changes were made to sample size, study design, study arms, and analytical methods, all before the data lock/unblinding. In all cases, justification for the changes was documented in the trial protocol or SAP, signed off by the trial biostatistician and principal investigator, and reviewed/approved by an institutional review board, data and safety monitoring board, or sponsor. We recommend that SAP changes can be acceptable up to the time of data lock/unblinding. To maintain full transparency and necessary rigor, clear documentation of such changes should include details, rationale, date(s) such changes were implemented, and evidence of approval by relevant oversight bodies.

Recommendations for monitoring adherence and fidelity in pragmatic trials based on experience in the Pain Management Collaboratory.

Most pragmatic trials follow the PRagmatic Explanatory Continuum Indicator Summary (PRECIS-2) criteria. The criteria specify unobtrusive measurement of participants' protocol adherence and practitioners' intervention fidelity but suggest no special monitoring strategies to assure trial integrity. We present experience with adherence/fidelity monitoring in the Pain Management Collaboratory (PMC) and provide recommendations for their monitoring in pragmatic trials to preserve inferences of treatment comparisons. In November 2021, we surveyed 10 of 11 originally funded PMC pragmatic trials to determine the extent to which adherence and fidelity data were being monitored. Of the 10 PMC trials, 8 track adherence/fidelity. The electronic health record is the most frequent source for monitoring adherence (7/10) and fidelity (5/10). Most adherence data are used to monitor participant engagement with the trial intervention (4/10) and are reviewed by study teams (8/10) and often with a data and safety monitoring board (DSMB) (5/10). Half of the trials (5/10) reported using fidelity data for feedback/training; such data are not shared with a DSMB (0/10). Only 2 of 10 trials reported having prespecified guidance or rules around adherence/fidelity (eg, stopping rules or thresholds for corrective action, such as retraining). As a best practice for pragmatic trials, we recommend early and regular adherence/fidelity monitoring to determine whether intervention delivery is as intended. We propose a 2-stage process with thresholds for intervening and triggers for conducting a formal futility analysis if adherence and fidelity are not maintained. The level of monitoring should be unobtrusive for both participants and those delivering the intervention; resulting data should be reviewed by an independent DSMB.

Utility of the PICOTS framework to assess clinical trial disruptions: monitoring the impact of COVID-19 in the Pain Management Collaboratory.

Despite careful design of clinical trials, unforeseen disruptions can arise. The PICOTS (Patient population, Intervention, Comparator, Outcomes, Timepoints, Setting) framework was used to assess disruptions in pain management research imposed by coronavirus disease 2019 (COVID-19) within the Pain Management Collaboratory. Rapid qualitative methods were employed to identify trial disruptions due to COVID-19 in 11 pragmatic clinical trials of nonpharmacological approaches for pain management. The PICOTS framework was applied by investigators of 4 Collaboratory trials selected to cover 4 types of trial designs (individually randomized, stepped-wedge, cluster, sequential multiple assignment randomized trial-SMART). Interviews with the lead investigators of these trials were completed, and findings were presented/discussed on video calls over a 6-month period (March-August 2021) from which themes/lessons learned were identified and consensus reached. Investigators indicated that patient populations remained generally stable. A major COVID-19 trial disruption was moving from in-person to virtual care affecting delivery of interventions/comparators and outcome assessments. The resultant mixed-mode of care delivery created issues with intervention fidelity posing analytic challenges. COVID-19 also induced ongoing/intermittent delays and other barriers to accessing primary and specialty care at some facilities, creating research capacity issues affecting delivery of experimental interventions requiring sustained, reliable participation of clinical partners. Study designs most affected by COVID-19 were stepped-wedge (intervention/comparator changing over time), cluster (increased site variability inflating intracluster correlation), and SMART (second-stage randomizations disrupted); stratified individually-randomized trials were less vulnerable because of individual-level randomization. PICOTS provides a framework for assessing the impact of trial disruptions in a structured manner. Given the COVID-19 experience, it is important for researchers to consider the potential impact of future trial disruptions during study planning.

Optimizing diversity, equity and inclusion in pragmatic clinical trials: Findings from the Pain Management Collaboratory

The National Institutes of Health, U.S. Department of Defense, and U.S. Department of Veterans Affairs established a Pain Management Collaboratory (PMC) in 2017, with the purpose of implementing and evaluating nonpharmacological approaches for management of pain and co-occurring conditions in military and veteran healthcare systems through the execution of pragmatic clinical trials. The purpose of the current study is to detail and critically examine recruitment and retention procedures across the PMC’s large-scale multi-site pragmatic clinical trials, with attention to efforts made by trialists to diversify their study samples. Team members from 11 pragmatic clinical trials completed semi-structured interviews that focused on the meaning of diversity to the trial teams when planning the composition of their samples, methods used to recruit and retain diverse samples of patients, and planned analyses that take into consideration diverse subgroups of patients. Nearly 18,000 patients have been enrolled across trials, 22 % of whom were assigned female sex at birth and 34 % of whom identify with a marginalized race or ethnicity. Respondents highlighted study site selection, formation of partnerships with patient groups, and leveraging of data informatics as strategies that aided in the recruitment of patients diverse in terms of birth sex, race, and ethnicity. Notably, trialists adopted a narrow definition of diversity that did not take into consideration multiple intersecting identities of trial participants. Based on experiences of the PMC, we provide 14 recommendations on ways to diversify patient samples in clinical pain research. PerspectiveThis article describes challenges posed, and opportunities provided, with pain pragmatic clinical trial designs, emphasizing approaches that optimize the inclusion of social identity groups that have historically been under-represented in pain research.

Introduction: Pain Management Collaboratory: updates, lessons learned, and future directions

Introduction: Pain Management Collaboratory: updates, lessons learned, and future directions

Impact of the COVID-19 pandemic on participants in pragmatic clinical trials for chronic pain: implications for trial outcomes and beyond.

The COVID-19 pandemic had profound effects on society, including those living with chronic pain. This study sought to examine pandemic impacts on individuals enrolled in pragmatic clinical trials focused on nonpharmacological treatments for chronic pain. We evaluated responses to a questionnaire on COVID-19 impacts that had been administered to participants (n=2024) during study enrollment in 3 pragmatic clinical trials for chronic pain treatment. All trials were part of the National Institutes of Health (NIH)-Department of Veterans Affairs (VA)-Department of Defense (DOD) Pain Management Collaboratory. COVID-19-related impacts on access to health care, mental health, finances, ability to meet basic needs, and social support were assessed. Pandemic impacts were found in all domains assessed, including access to health care, mental and emotional health, ability to meet basic needs, finances, and social support. Impacts varied by demographic and clinical characteristics. The participants most negatively impacted by the pandemic were younger, Black or Latino, female, more educated, and unemployed and had screened positive for depression. No impact differences were found with regard to alcohol use disorder screenings or a prior history of COVID-19. Higher levels of pain were associated with worse pandemic impacts, and negative impacts declined over time. Negative impacts of the pandemic on individuals living with chronic pain cut across aspects of life that are also central to effective pain management, including access to health care, social support, and mental and emotional health, with differential impacts found across key demographic and clinical factors. These findings should yield consideration of pandemic impacts in clinical practice and as moderating effects of treatment outcomes in clinical trials conducted during the pandemic.

Strategies for working with pragmatic clinical trial observational data-lessons learned from the Pain Management Collaboratory.

Strategies for working with pragmatic clinical trial observational data-lessons learned from the Pain Management Collaboratory.

Challenges in clinical data sharing-experiences of the pain management collaboratory.

Challenges in clinical data sharing-experiences of the pain management collaboratory.

Engaging clinical partners in pragmatic clinical trials: lessons learned from the pain management collaboratory.

Engaging clinical partners in pragmatic clinical trials: lessons learned from the pain management collaboratory.

TIDieR-telehealth: precision in reporting of telehealth interventions used in clinical trials - unique considerations for the Template for the Intervention Description and Replication (TIDieR) checklist

BackgroundRecent international health events have led to an increased proliferation of remotely delivered health interventions. Even with the pandemic seemingly coming under control, the experiences of the past year have fueled a growth in ideas and technology for increasing the scope of remote care delivery. Unfortunately, clinicians and health systems will have difficulty with the adoption and implementation of these interventions if ongoing and future clinical trials fail to report necessary details about execution, platforms, and infrastructure related to these interventions. The purpose was to develop guidance for reporting of telehealth interventions.MethodsA working group from the US Pain Management Collaboratory developed guidance for complete reporting of telehealth interventions. The process went through 5-step process from conception to final checklist development with input for many stakeholders, to include all 11 primary investigators with trials in the Collaboratory.ResultsAn extension focused on unique considerations relevant to telehealth interventions was developed for the Template for the Intervention Description and Replication (TIDieR) checklist.ConclusionThe Telehealth Intervention guideline encourages use of the Template for the Intervention Description and Replication (TIDieR) checklist as a valuable tool (TIDieR-Telehealth) to improve the quality of research through a reporting guide of relevant interventions that will help maximize reproducibility and implementation.

Optimizing the Impact of Pragmatic Clinical Trials for Veteran and Military Populations: Lessons From the Pain Management Collaboratory.

Pragmatic clinical trials (PCTs) are well-suited to address unmet healthcare needs, such as those arising from the dual public health crises of chronic pain and opioid misuse, recently exacerbated by the COVID-19 pandemic. These overlapping epidemics have complex, multifactorial etiologies, and PCTs can be used to investigate the effectiveness of integrated therapies that are currently available but underused. Yet individual pragmatic studies can be limited in their reach because of existing structural and cultural barriers to dissemination and implementation. The National Institutes of Health, Department of Defense, and Department of Veterans Affairs formed an interagency research partnership, the Pain Management Collaboratory. The partnership combines pragmatic trial design with collaborative tools and relationship building within a large network to advance the science and impact of nonpharmacological approaches and integrated models of care for the management of pain and common co-occurring conditions. The Pain Management Collaboratory team supports 11 large-scale, multisite PCTs in veteran and military health systems with a focus on team science with the shared aim that the "whole is greater than the sum of the parts." Herein, we describe this integrated approach and lessons learned, including incentivizing all parties; proactively offering frequent opportunities for problem-solving; engaging stakeholders during all stages of research; and navigating competing research priorities. We also articulate several specific strategies and their practical implications for advancing pain management in active clinical, "real-world," settings.

Assessing the impact of the COVID-19 pandemic on pragmatic clinical trial participants

Characterizing the impacts of disruption attributable to the COVID-19 pandemic on clinical research is important, especially in pain research where psychological, social, and economic stressors attributable to the COVID-19 pandemic may greatly impact treatment effects. The National Institutes of Health – Department of Defense – Department of Veterans Affairs Pain Management Collaboratory (PMC) is a collective effort supporting 11 pragmatic clinical trials studying nonpharmacological approaches and innovative integrated care models for pain management in veteran and military health systems. The PMC rapidly developed a brief pandemic impacts measure for use across its pragmatic trials studying pain while remaining broadly applicable to other areas of clinical research. Through open discussion and consensus building by the PMC's Phenotypes and Outcomes Work Group, the PMC Coronavirus Pandemic (COVID-19) Measure was iteratively developed. The measure assesses the following domains (one item/domain): access to healthcare, social support, finances, ability to meet basic needs, and mental or emotional health. Two additional items assess infection status (personal and household) and hospitalization. The measure uses structured responses with a three-point scale for COVID-19 infection status and four-point ordinal rank response for all other domains. We recommend individualized adaptation as appropriate by clinical research teams using this measure to survey the effects of the COVID-19 pandemic on study participants. This can also help maintain utility of the measure beyond the COVID-19 pandemic to characterize impacts during future public health emergencies that may require mitigation strategies such as periods of quarantine and isolation.

Development and Implementation of the Military Treatment Facility Engagement Committee (MTFEC) to Support Pragmatic Clinical Trials in the Military Health System.

Within the population of military service members and veterans, chronic pain is highly prevalent, often complex, and frequently related to traumatic experiences that are more likely to occur to members of this demographic, such as individuals with traumatic brain injury or limb loss. In September 2017, the National Institutes of Health (NIH), Department of Defense (DOD), and Department of Veterans Affairs (VA) Pain Management Collaboratory (PMC) was formed as a significant and innovative inter-government agency partnership to support a multicomponent research initiative focusing on nonpharmacological approaches for pain management addressing the needs of service members, their dependents, and veterans. A Pain Management Collaboratory Coordinating Center (PMC3) was also established to facilitate collective learning across 11 individually funded pragmatic clinical trials (PCTs) designed to optimize the impact of the PMC as an integrated whole. Although the DOD and VA health care systems are ideal sites for the enactment of PCTs, executing these trials within the local context of DOD military treatment facilities (MTFs) can present unique challenges. The Military Treatment Facility Engagement Committee (MTFEC) was created to support the efforts of the PMC3 in its role as a national resource for development and refinement of innovative tools, best practices, and other resources in the conduct of high impact PCTs. The MTFEC is composed of experts from each service who bring experiences in executing clinical pain management trials that can enhance the planning and execution of the PCTs. It provides expertise and leadership in the execution of research studies at within MTFs and within the DOD health care system, with guidance from PMC3 Directors and in collaboration with NIH, DOD, and VA program and scientific officers. Considering the importance of enacting large-scale, pragmatic studies to implement effective strategies in clinical practice for chronic pain management, the MTFEC has begun to actualize its purpose by identifying potential barriers and challenges to study implementation and exploring how the PMC can support and aid in the execution of PCTs by applying similar approaches to stakeholder and subject matter engagement for their research.

Stakeholder Engagement in Pragmatic Clinical Trials: Emphasizing Relationships to Improve Pain Management Delivery and Outcomes.

The NIH-DOD-VA Pain Management Collaboratory (PMC) supports 11 pragmatic clinical trials (PCTs) on nonpharmacological approaches to management of pain and co-occurring conditions in U.S. military and veteran health organizations. The Stakeholder Engagement Work Group is supported by a separately funded Coordinating Center and was formed with the goal of developing respectful and productive partnerships that will maximize the ability to generate trustworthy, internally valid findings directly relevant to veterans and military service members with pain, front-line primary care clinicians and health care teams, and health system leaders. The Stakeholder Engagement Work Group provides a forum to promote success of the PCTs in which principal investigators and/or their designees discuss various stakeholder engagement strategies, address challenges, and share experiences. Herein, we communicate features of meaningful stakeholder engagement in the design and implementation of pain management pragmatic trials, across the PMC. Our collective experiences suggest that an optimal stakeholder-engaged research project involves understanding the following: i) Who are research stakeholders in PMC trials? ii) How do investigators ensure that stakeholders represent the interests of a study's target treatment population, including individuals from underrepresented groups?, and iii) How can sustained stakeholder relationships help overcome implementation challenges over the course of a PCT? Our experiences outline the role of stakeholders in pain research and may inform future pragmatic trial researchers regarding methods to engage stakeholders effectively.

Strategy for addressing research-site overlap in pragmatic clinical trials: lessons learned from the NIH-DOD-VA Pain Management Collaboratory (PMC)

BackgroundThe Pain Management Collaboratory (PMC) is a multi-site network of pragmatic clinical trials (PCTs) focused on nonpharmacological approaches to pain management, conducted in health care systems of the US Department of Defense (DoD) and Department of Veterans Affairs (VA) and co-funded by the National Institutes of Health (NIH). Concerns about potential research-site overlap prompted the PMC investigator community to consider strategies to avert this problem that could negatively affect recruitment and contaminate interventions and thus pose a threat to trial integrity.MethodsWe developed a two-step strategy to identify and remediate research-site overlap by obtaining detailed recruitment plans across all PMC PCTs that addressed eligibility criteria, recruitment methods, trial settings, and timeframes. The first, information-gathering phase consisted of a 2-month period for data collection from PIs, stakeholders, and ClinicalTrials.gov. The second, remediation phase consisted of a series of moderated conference calls over a 1-month time period to develop plans to address overlap. Remediation efforts focused on exclusion criteria and recruitment strategies, and they involved collaboration with sponsors and stakeholder groups such as the Military Treatment Facility Engagement Committee (MTFEC). The MTFEC is comprised of collaborating DoD and university-affiliated PIs, clinicians, and educators devoted to facilitating successful pragmatic trials in DoD settings.ResultsOf 61 recruitment sites for the 11 PMC PCTs, 17 (28%) overlapped. Four PCTs had five overlapping Military Treatment Facilities (MTFs), and eight PCTs had 12 overlapping VA Medical Centers (VAMCs). We developed three general strategies to avoid research-site overlap: (i) modify exclusion criteria, (ii) coordinate recruitment efforts, and/or (iii) replace or avoid any overlapping sites. Potential overlap from competing studies outside of the PMC was apparent at 26 sites, but we were not able to confirm them as true conflicts.ConclusionProactive strategies can be used to resolve the issue of overlapping research sites in the PMC. These strategies, combined with open and impartial mediation approaches that include researchers, sponsors, and stakeholders, provide lessons learned from this large and complex pragmatic research effort.

Adapting to disruption of research during the COVID-19 pandemic while testing nonpharmacological approaches to pain management.

The COVID-19 pandemic has slowed research progress, with particularly disruptive effects on investigations of addressing urgent public health challenges, such as chronic pain. The National Institutes of Health (NIH) Department of Defense (DoD) Department of Veterans Affairs (VA) Pain Management Collaboratory (PMC) supports 11 large-scale, multisite, embedded pragmatic clinical trials (PCTs) in military and veteran health systems. The PMC rapidly developed and enacted a plan to address key issues in response to the COVID-19 pandemic. The PMC tracked and collaborated in developing plans for addressing COVID-19 impacts across multiple domains and characterized the impact of COVID-19 on PCT operations, including delays in recruitment and revisions of study protocols. A harmonized participant questionnaire will facilitate later meta-analyses and cross-study comparisons of the impact of COVID-19 across all 11 PCTs. The pandemic has affected intervention delivery, outcomes, regulatory and ethics issues, participant recruitment, and study design. The PMC took concrete steps to ensure scientific rigor while encouraging flexibility in the PCTs, while paying close attention to minimizing the burden on research participants, investigators, and clinical care teams. Sudden changes in the delivery of pain management interventions will probably alter treatment effects measured via PMC PCTs. Through the use of harmonized instruments and surveys, we are capturing these changes and plan to monitor the impact on research practices, as well as on health outcomes. Analyses of patient-reported measures over time will inform potential relationships between chronic pain, mental health, and various socioeconomic stressors common among Americans during the COVID-19 pandemic.

NIH-DoD-VA Pain Management Collaboratory.

NIH-DoD-VA Pain Management Collaboratory.