Conduct of Large, Multisite, Comparative Clinical Effectiveness Research Studies
Learnings From the Patient-Centered Outcomes Research Institute’s Palliative Care Learning Network
Bibliographic Data
Adults with advanced illnesses, as well as their caregivers, experience a high burden of physical and psychosocial symptoms. Individuals who receive palliative care services addressing these symptoms report improved quality of life as well as fewer hospitalizations and emergency department visits.1 However, access to palliative care services is often limited to inpatient hospitals and hospice settings, and many patients and their caregivers report unmet needs for these services in their communities. Since 2010, The Patient-Centered Outcomes Research Institute (PCORI), a non-profit, independent nongovernmental organization, has supported the generation of high-quality clinical evidence through the funding of comparative clinical effectiveness research (CER) designed to help patients and other stakeholders make better-informed decisions.2 Central to PCORI’s approach is a transparent, rigorous process that emphasizes patient and stakeholder engagement to inform PCORI’s priorities and enhance its work. To date, PCORI has invested $311.2 million in 68 studies focused on adults living with advanced illnesses across investigator-initiated and focused CER funding mechanisms. In 2016, to identify opportunities to build on initial investments in investigator-initiated palliative care research, PCORI convened a 1-day in-person stakeholder workshop in Washington, DC, attended by over 80 stakeholders representing patients with advanced illness, caregivers, clinicians, and others, to identify the most important evidence gaps and prioritize comparative effectiveness research questions for patient-centered palliative care delivery among adults with advanced illnesses and their caregivers.3 The subsequent year, PCORI invested more than $80 million through 9 contract awards to compare the effectiveness of different established models for delivering palliative care and advance care planning (ACP) in the community setting.4 Collectively, these studies aim to improve care delivery and health outcomes for people living with advanced illnesses and their caregivers, given the expanded need for palliative care due to the aging population and increasing prevalence of serious and advanced illnesses.5 Recognizing the opportunity to leverage the simultaneous funding of this cohort of multisite clinical trials with a similar focus, PCORI also created a Palliative Care Learning Network (PCLN) in an effort to support the success of the awardees in the conduct of these studies and to maximize their collective scientific impact. Since the inception of the learning network, PCORI has also funded another large-scale palliative care trial through the Phased Large Awards for Comparative Effectiveness Research (PLACER) mechanism. This funding mechanism is intended to support impactful, large-scale trials that merit initial testing and refinement to determine the feasibility of trial success. Considering the potential benefit participation in the learning network could have for this study and team, in 2022, this study was added to the learning network, bringing the total number of participating studies to 10. Through the PCLN, awardees conducting these trials have had ongoing interactions, shared study progress to date, worked to troubleshoot common study challenges both in general and specifically related to the impact of COVID-19 on their studies, and developed collaborative products relevant to advancing the field of palliative care research and practice. PCORI contracted with a research organization, Westat, to facilitate and support all the activities of the PCLN. OVERVIEW AND SUMMARY OF FUNDED STUDIES Collectively, the 10 funded studies are some of the largest and most complex multisite community-based CER trials in the field of palliative care to date. Three studies were designed to test ACP strategies, while 7 focused on evaluating various established models for delivering palliative care services (see Table 1 for a brief description of the studies). Each study evaluates both patient and caregiver outcomes, and together, these trials include a broad range of health conditions, interventions, modalities, and settings of care.6 TABLE 1 - Synopsis of Funded Studies Models of palliative care studies Principal investigator(s): Rebecca Aslakson, MD, PhD, and Karl Lorenz, MD, MSHS Research Question: What is the comparative effectiveness of surgeon–palliative care team co-management vs. surgeon management alone on patient- and caregiver-centered outcomes among patients undergoing major cancer surgery and their caregivers? Status: Completed Principal Investigator(s): Corita Grudzen, MD and Keith Goldfeld, DrPH Research Question: What is the comparative effectiveness of palliative care delivered by a nurse-led telephonic case–management model vs. in-person, outpatient specialty palliative care on patient- and caregiver-centered outcomes among patients with advanced illnesses who are discharged to home after an emergency department visit and their caregivers? Status: Completed Principal Investigator(s): Areej El-Jawahri, MD and Jennifer Temel, MD Research Question: Is primary palliative care delivered by an oncology clinician who has undergone palliative care training an effective alternative strategy to palliative care delivered by a specialty palliative care clinician for patients with acute myelogenous leukemia (AML)? Status: Active Principal Investigator(s): Susan Enguidanos, PhD, MPH Research Question: What is the comparative effectiveness of home-based palliative care (HBPC) vs. enhanced usual primary care (EUC) among patients with advanced serious illnesses on patient symptoms, depression, anxiety, healthcare utilization, survival, and caregiver outcomes? Status: Completed (CER trial not completed as intended)* Principal Investigator(s): Huong Nguyen, PhD, RN and Richard Mularski, MD Research Question: What is the comparative effectiveness of a tech-supported home-based palliative care (HBPC) model that promotes early remote access to a provider while the nurse was in the patient’s home compared to a standard HBPC model that included routine home visits by a nurse and provider? Status: Completed (CER trial not completed as intended)* Principal Investigator(s): Victor Navarro, MD and Manisha Verma, MD, MPH Comparative effectiveness research question: What is the comparative effectiveness of palliative care delivered by board-certified palliative care specialists vs. hepatologists trained in palliative care on patient- and caregiver-centered outcomes among patients with end-stage liver disease and their caregivers? Status: Active Principal Investigator(s): Jennifer Temel, MD and Joseph Greer, PhD, MS Comparative effectiveness research question: What is the comparative effectiveness of early integration of palliative care delivered by palliative care specialists through telemedicine vs. in-person clinic visits on patient- and caregiver-centered outcomes among patients newly diagnosed with advanced lung cancer and their caregivers? Status: Active Advance care planning studies Principal Investigator(s): Kimberly Johnson, MD Comparative effectiveness research question: What is the comparative effectiveness of a structured ACP approach (Respecting Choices) vs. a patient-guided self-management approach (Five Wishes) in facilitating formal or informal ACP within racial subgroups of patients and in reducing racial disparities between these groups on patient- and caregiver-centered outcomes among older adult patients with advanced illnesses and their caregivers? Status: Active Principal Investigator(s): Annette M. Totten, PhD, MPA and France Légaré, MD, PhD Comparative effectiveness research question: What is the comparative effectiveness of a team-based vs. singular clinician approach to advance care planning using the Serious Illness Care Program in the primary care setting among patients with advanced illnesses and their caregivers? Status: Completed Principal Investigator(s): Neil Wenger, MD, MPH, and Anne Walling, MD, PhD Comparative effectiveness research question: What is the comparative effectiveness of three different approaches to ACP on patient-centered outcomes such as Advance Directive completion and goal-concordant care? Status: Active *While the CER trials could not be completed, the study teams published multiple manuscripts documenting valuable lessons learned that could benefit researchers, health systems, and payers As of April 2024, 3 of the 10 clinical trials are completed. Five trials are in different phases of active implementation, ranging from patient and caregiver enrollment to data analysis. These studies are expected to be completed within the next 1 to 3 years. The remaining 2 trials, both focusing on the delivery of home-based palliative care, had to be stopped prior to the COVID-19 pandemic for a variety of reasons, including challenges in recruitment and implementation of intervention per protocol, and shift in institutional priorities resulting from changes in Medicare payment policies during the study period.7,8 These projects, nevertheless, made significant contributions to the field by exploring key barriers and facilitators to the delivery of high-quality home-based palliative care and challenges in conducting large multisite trials in a seriously ill patient population.9,10 Collectively, these studies include 175 study sites, with each study ranging from 5 to 50 sites across a variety of settings, including primary and specialty outpatient care, emergency departments, and hospitals. Among the cohort of 8 studies that will complete the CER trial, 5 are cluster randomized at the clinician, clinic, or health system level, and the remaining 3 are individually randomized. There is broad inclusion of patients with various advanced or end-stage conditions across several of the studies, but specific to each kind of advanced illness, cancer is the most common condition of focus (7 studies), followed by advanced heart failure, advanced chronic obstructive pulmonary disease, and advanced liver or kidney disease, which are included in 3 studies each. Quality of life is the most commonly assessed primary outcome (5 studies), followed by goal-concordant care and ACP documentation in 2 studies each and days at home in one study. All studies assess caregiver outcomes to varying extents. For additional detail, please see prior published protocols.6,11 SUMMARY OF STUDY CHANGES AND UPDATES Due to the inherent complexity of conducting large, multisite trials on palliative care models and ACP interventions, as well as the COVID-19 pandemic, the study teams have encountered and overcome numerous challenges while conducting these trials. In some cases, these challenges resulted in the studies making implementation and timeline changes. During the initial start-up and implementation phases, many studies required greater time and resource investment than anticipated on study operations and process issues. These issues included logistical challenges with handling institutional review board (IRB) approval for multiple sites, coordinating participant recruitment and intervention implementation across multiple sites, addressing turnover among site staff, replacing or adding sites, and determining optimal site payment models, for example. Collectively, these challenges, in some cases, led to the studies being delayed in starting recruitment and prolonged site recruitment periods. With the onset of the COVID-19 pandemic in early 2020, the studies were faced with unparalleled challenges, resulting in some studies having to pause certain sites or study arms or temporarily suspend study activities. All the studies that were in active implementation during the pandemic were affected, but the nature and extent of these effects differed based on numerous factors, including, for example, the geographic locations of the study, types of study sites, intervention delivery modalities, and study hypothesis. PCORI staff worked closely with investigators to assess and accommodate the need for modifications to study procedures, timeline, and, when appropriate, budgets. Studies made changes to data collection methods, such as allowing verbal or remote consent, switching from in-person to virtual data collection, and creating new methods for identifying eligible patients. Most studies also made appropriate changes to their study settings. In general, these changes involved allowing the intervention delivery to occur in a different setting (eg, telephonic or remotely vs. in-person at a clinic, hospital, or other community setting). Other types of adaptations included changing the follow-up period or making study-specific intervention changes. Feedback from the awardees indicates that the study modifications made as a result of COVID-19 have generally proven to be beneficial for ongoing study operations, and awardees generally retained the modifications made as a result of the pandemic. While these changes to the implementation of the interventions were approved by PCORI when appropriate, all study teams were required to pay special attention to assessing the fidelity of intervention delivery overtime. In addition to study modifications made as a result of COVID-19, awardees also grappled with the analytic sequelae of the pandemic, including approaches for measuring COVID-19-related study contamination, assessing the impact of COVID-19 on baseline patient-reported outcomes, as well as high proportions of missing data due to multiple factors, including the COVID-19 pandemic, the multisite nature of the studies, and the severity of patient illness. The study teams have navigated and continue to address these operational and pandemic-related factors, which have necessitated study implementation and timeline adaptations. Seven requested study extensions, resulting in the study research periods being extended between 7 and 24 months. The research periods for these seven studies, which were originally all to conclude between July 2021 and July 2023, will conclude between October 2022 and March 2025. The large trial that PCORI funded in 2021 recently concluded its feasibility phase and began its full-scale phase research period, which will run until November 2028. The manuscripts in this topical collection provide detailed insights and shared learnings from study investigators on their experiences of navigating these challenges. CONTRIBUTIONS OF THE PCLN STUDIES IN CONDUCTING PALLIATIVE CARE RESEARCH The collective experiences of these PCORI awardees provide insights into the factors that affect the implementation of large-scale palliative care trials and the meaningful engagement of patients and other stakeholders in the research process. At the time the majority of these studies were funded in 2017, they were some of the most complex and largest trials funded in terms of scope and budget (direct costs ranged from $6 million to $10 million over a 5-year funding period). Based on lessons learned from the funding of large, complex clinical trials such as these and others that PCORI has funded overtime, PCORI has increased budget limits for many of our standing funding announcements and developed the PLACER mechanism for large, complex studies that address highly impactful questions, that includes an initial feasibility phase, before the funding of the full-scale clinical trial. Since the first issuance of the PLACER funding announcement in 2020, 2 large palliative care trials have been funded under this mechanism. The collective experiences of these study teams to engage multidisciplinary stakeholder partners at various stages of the research process, along with similar efforts by other PCORI-funded investigators, have also informed PCORI’s ongoing efforts to advance the science of stakeholder engagement. Through the PCLN, awardees of these 10 palliative care clinical trials have been able to share their experiences with and learn from each other to address study challenges. The PCLN has also provided a valuable mechanism to chronicle and summarize these learnings. This topical collection is a product of the PCLN’s efforts, sharing lessons learned across 3 key areas: monitoring intervention implementation and fidelity, conducting multisite palliative care studies, and engaging stakeholders in palliative care studies. The study teams identified these topics as being integral to the implementation of palliative care-focused clinical trials and areas where the field of palliative care research can benefit from their collective learning. First, the intervention implementation and fidelity article discusses themes around implementing complex palliative care interventions across multiple healthcare delivery sites and systems and describes the different approaches taken by the studies to define and monitor intervention fidelity. Second, the conducting multisite palliative care studies article provides specific, granular guidance for future multisite palliative care trials based on the PCLN studies’ experiences in the launch and execution of their multisite studies. Finally, the Stakeholder Engagement in palliative care research studies article focuses on stakeholder engagement from the point of view of the study team (as opposed to the viewpoint of different stakeholder groups) and highlights their views of how they advanced the practice of engagement in their studies. This paper complements other efforts to synthesize learnings from the experiences of different stakeholder partners in collaborating with research teams on CER studies aimed at addressing important patient-centered research questions.12–16 These 3 articles, each co-authored by members of multiple study teams, offer a unique perspective resulting from the different teams collaborating with each other to synthesize and distill their collective experiences across the entire cohort of PCORI-funded palliative care studies participating in the PCLN. The detailed reflections and learnings of the study teams discussed in these papers provide insights to support future patient-centered palliative care research and have the potential to inform more efficient and effective uptake of palliative care interventions in clinical practice
Alternative medicine · Comparative effectiveness research · MEDLINE · Pathology · Political science · Frailty in Older Adults · Health Systems, Economic Evaluations, Quality of Life · Medicine · Palliative Care and End-of-Life Issues
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