Engaging Stakeholders in the Design and Conduct of Embedded Pragmatic Clinical Trials for Alzheimer’s Disease and Alzheimer’s Disease-Related Dementias

Abstract

Embedded pragmatic clinical trials (ePCTs) of non-drug interventions for Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD) are conducted in real-world clinical settings and designed to generate evidence base to inform clinical and policy decisions about care for this vulnerable population. ePCTs exist within a complex ecosystem of relationships between researchers, payors, policy makers, healthcare systems, direct care staff, advocacy groups, families, caregivers, and people living with dementia (PLWD). Because the rapid increase of the number of Americans with AD/ADRD outpaces curative treatments, there is an urgent need to mobilize the power of these relationships to improve dementia care and address a mounting public health crisis. Stakeholder engagement in ePCTs is essential to generate research questions, establish the relevancy of trials to the intended end-users, and to understand factors that influence dissemination and implementation in real-world clinical settings. The process of including stakeholders in ePCTs for dementia is similar to stakeholder engagement in ePCTs for other diseases and conditions, however the unique nature of embedded research, prevalence of caregiver and provider burden, and the progressive worsening of cognitive impairment in PLWD must be approached with additional strategies. This paper presents key considerations of stakeholder engagement for ePCTs in AD/ADRD and main activities of the Stakeholder Engagement Team in the NIA IMPACT Collaboratory to move the field forward.

Introduction

Embedded pragmatic clinical trials (ePCTs) of non-drug interventions for Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD) are conducted in real-world settings and designed to generate high-quality evidence to inform decisions about effective care for this vulnerable population. ePCTs exist within a complex ecosystem of relationships among researchers, payors, policy makers, healthcare systems, direct care staff, advocacy groups, families, caregivers, and people living with dementia (PLWD). Because the rapid increase in the number of Americans with AD/ADRD significantly outpaces curative treatments, there is an urgent need to mobilize the power of these relationships to improve care and address a growing public health crisis. From generating research questions and establishing relevancy of trials with end-users, to understanding factors influencing dissemination and implementation in real-world clinical settings, stakeholder engagement in ePCTs focused on AD/ADRD is essential to advance progress in dementia care.

The process of including stakeholders in ePCTs for dementia is similar to stakeholder engagement in ePCTs for other diseases and conditions. However, the unique prevalence of high levels of caregiver and provider burden, and the progressive worsening of cognitive impairment in PLWD, require additional strategies. Stakeholders, including PLWD, caregivers, direct care staff, clinicians, health system leaders and payors must also be strategically included in these embedded trials in order to assure protocols are realistic in real-world settings and lead to the adoption of promising interventions amidst complex workflows and changing organizational cultures and healthcare environments.

This manuscript describes approaches to stakeholder engagement in ePCTs for AD/ADRD. We begin with an overview of the origins of stakeholder engagement in research and its emerging evidence base in embedded pragmatic clinical trials (ePCTs). Next, we describe how current frameworks for stakeholder engagement are underspecified and must be adapted for use in AD/ADRD. We detail the unique considerations and complexities of stakeholder engagement in ePCTs for AD/ADRD. We conclude by describing what we consider to be important stakeholder groups, engagement processes for ePCT’s on AD/ADRD, and the approach to stakeholder engagement to be used by the National Institute on Aging (NIA) IMbedded Pragmatic Alzheimers disease (AD) and AD Related Dementias (AD/ADRD) Clinical Trials (IMPACT) Collaboratory. The goal of the Collaboratory is to build the nation’s capacity to conduct pragmatic clinical trials of non-pharmacological interventions embedded within healthcare systems for PLWD and their caregivers.

ePCTs conducted in real-world settings mandate collaboration throughout the entire research process among a variety of stakeholders. Thus, the Collaboratory has embedded stakeholder engagement as one of its foundational pillars and delegated the formal coordination of activities to the Stakeholder Engagement Team (SET). The role of the SET is to guide and support investigators with engagement activities in the conduct of ePCTs, develop and disseminate guidance and training materials about engagement, and maintain a Stakeholder Advisory Committee to advise the Collaboratory about SE activities and priorities for research (see Table 1).

Table 1:

Objectives and Activities of Stakeholder Engagement Team in NIA IMPACT Collaborator

Objectives of Stakeholder Engagement Team	Specific Activities
1. Guides and, supports investigators conducting ePCTs among PLWD and their caregivers in stakeholder engagement activities.	Assist with selection of applications to pilot grant award program to assess the strength of relevant stakeholder engagement domains (feasibility to implement, cost, acceptability to providers, alignment with stakeholder priorities). Support selected pilot investigators in optimizing ePCT design through navigation process.
2. Develops and disseminates guidance and training materials about engaging stakeholders in the conduct of ePCTs among PLWD and their caregivers with healthcare systems.	Collaborate with PCRO and Alzheimer’s Association to recruit PLWD, Family Caregivers, and Representatives for People Living with Moderate-to-Severe Dementia for a Lived Experience Panel to identify patient-centered outcomes. Develop and disseminate training materials to build competencies in stakeholder engagement for pragmatic trialists in AD/ADRD
3. Convenes a Stakeholder Advisory Committee that advises the NIA IMPACT Collaboratory about stakeholder engagement activities, strategies to assist investigators with stakeholder engagement, and priority topics for the development of guidance materials.	Identify and synthesize stakeholder priorities for research. Describe best practices for strategies to engage healthcare system leaders and clinicians during development and implementation of ePCTs.

Origins of Stakeholder Engagement in Research

Stakeholder engagement in health research is connected to a decades-long tradition of community-based participatory research¹ as well to international stakeholder engagement activities that have emerged over the last 20 years.^2-5 Community-Based Participatory Research began with an ethos of community advocacy and democratic questioning about fairness and representation in clinical research. The concept of “citizen control” has taken root in public policy⁶ and now influences the relationship between clinical research subjects and researchers.

International organizations such as INVOLVE,^2-4 in the United Kingdom, the Canadian Institutes of Health Research,⁷ and Patient Centered Outcomes Research Institute (PCORI)⁸ in the United States, have been influential in defining stakeholder groups and identifying principles and methods for engaging the public in healthcare research. Stakeholders are generally defined as individuals and organizations with an interest in the conduct and outcomes of health research.^9,10 A review of principles for research engagement¹¹ demonstrates convergence on the set of principles expressed by PCORI: trust, honesty, co-learning, transparency, reciprocal relationships, partnership, and respect.¹² While methods of engagement vary across disciplines and projects, these principles, particularly partnership and respect, continue to be prominent.

Stakeholder Engagement in ePCTs

ePCTs have emerged as part of a multi-faceted national strategy to reprogram our thinking about the design and conduct of clinical trials.¹³ The intention is to purposefully connect what have traditionally been two siloed worlds, scientific research and everyday clinical practice, in order to accelerate the generation and adoption of an evidence-base about what care works best and for whom when it is delivered and received in real world settings. Unlike a traditional clinical trial, which often originates from researchers alone, ePCTs are intended to improve policy and clinical decision making by answering questions that are relevant to patients, clinicians, and other healthcare decision makers.¹⁴ As such, engaging key stakeholders in identifying important research questions and designing ePCTs to effectively answer those questions is critical.

Recognizing the importance of stakeholder engagement in the design and implementation of ePCTs, the National Institutes of Health (NIH) Health Care Systems Research Collaboratory (HCS) Collaboratory¹³ established a Stakeholder Engagement Core as part of its original Collaboratory Coordinating Center in 2012. At that time, the field of stakeholder engagement in comparative effectiveness research was just beginning its rapid evolution, and empirical evidence related to engagement in ePCTs was lacking. Explicit guidance on how stakeholders should be engaged in ePCT demonstration projects supported by the NIH HCS Collaboratory was not provided. Rather, the first cohort of demonstration projects were viewed as a “learning lab” through which the Stakeholder Engagement Core could work to identify common challenges and convene a diverse Stakeholder Advisory Committee to discuss solutions.

Lessons learned from the NIH HCS Collaboratory, make clear that active engagement with stakeholders is integral to the success of ePCTs.¹⁵ The potential impacts of engagement include improving the relevancy of trials to multiple stakeholder groups, accelerating the uptake of research findings by end-users, speeding recruitment and enhancing retention, and understanding site-specific variables, such as organizational barriers and workplace culture, that can impact the conduct of ePCTs.^12,16,17

Stakeholder Engagement in ePCTs for AD/ADRD

In 2017, a public-private steering committee under the auspices of the National Alzheimer’s Project ACT (NAPA) Advisory Council convened a Research Summit to focus on Dementia Care, Services, and Supports.¹⁸ The Summit identified priorities for stakeholder engagement in research on AD/ADRD, beginning with the recommendation to engage PLWD and their caregivers as part of research teams. While research funded by PCORI carries such a requirement, the NIH and other major US funders do not include engagement as a requirement. The limited evidence base about engagement in dementia research is an opportunity for the NIA IMPACT Collaboratory to pursue and evaluate engagement in ePCTs for AD/ADRD. This research recommendation represents the start of a shift in culture about dementia research and highlights the need for evaluation of engagement to ensure best practices are identified and spread, with the recognition that some methods may be found to be ineffective for this population.

Much has been learned about stakeholder engagement in research^{12, 17,19} and in ePCTs¹⁵ specifically, over the past decade. However, in the course of evaluating current frameworks for stakeholder engagement for adoption by the Collaboratory, we noted that some frameworks are underspecified for use in ePCTs with AD/ADRD and must be adapted.

There are special considerations for involving PLWD and caregivers as stakeholders in research. For example, there is a need to match the capacity of PLWD with their abilities to participate as stakeholders. Some engagement frameworks appear to make assumptions about wellness and capacity for sustained engagement that may not be possible for PLWD as their cognitive symptoms progress. Given the prevalence and fluctuation of behavioral symptoms, such as agitation and aggression,^20,21 meaningful opportunities for flexible, transactional, intermittent, and sustained engagement are needed as symptoms and impairment fluctuate and progress. Identifying and ensuring well-being, including ethical well-being, avoiding paternalism, increasing representation of historically underrepresented groups, and acknowledging contributions in a way acceptable to those involved have also been noted in the literature.^22-24

Additionally, unique ethical considerations,²⁵ such as compensation for participation and the ability to provide consent, with the progression of AD/ADRD must be considered. While caregivers and legally authorized representatives can be consulted, concerns about responsibilities of proxy respondents when PLWD can no longer participate as stakeholders (e.g., substituted representation) and who has authority to speak on behalf of people living with moderate to severe dementia remain. Caregivers are unique in that they may be targets of an intervention themselves or may experience effects from interventions indirectly. Although the types of caregiver burdens associated with caring for PLWD are well-known,²⁶ we know very little about best models of engagement for caregivers of PLWD and how to avoid adding additional burdens.

An additional gap in existing models is the use of large categories to lump together stakeholder groups by type, such as “healthcare systems.” However, healthcare systems that provide care for PLWD are unique and varied. In addition to setting and site-specific factors that influence engagement activities and the conduct of ePCTs, there are barriers and facilitators for various stakeholder groups. For example, frontline providers and care staff caring for the complex needs of PLWD may have limited time to engage in research. Defining a clear return on investment for their engagement is often required. Frontline providers and care staff also have first-hand knowledge that is critical to successfully facilitate embedded ePCTs. By not calling out specific key players in ePCTs, these models risk overlooking the degree and kind of influence of sub-groups, like direct care staff, who often deliver the intervention in ePCTs, and have key insights into how best to adapt interventions.

Because ePCTs occur within healthcare systems and their respective social systems, while connecting the often siloed worlds of research and clinical practice, they require engagement of a wide range of stakeholder perspectives. Gaining permission from healthcare system leaders to embed a trial within a system is a necessary, but insufficient, form of engagement.

For stakeholder engagement to be most effective, it must occur trom the first stages of project design. Beginning with the generation of research questions, to establishing relevancy of proposed interventions to stakeholders, there is a need to understand from the outset how various groups perceive its potential to influence outcomes. Ultimately, the success of an ePCT is adoption of an intervention as standard practice for dementia care. Stakeholders can help anticipate barriers and unintended consequences based on real-world factors, such as cost, integration into existing workflows and patient preferences for outcomes.

Stakeholder Engagement in the NIA IMPACT Collaboratory

The NIA IMPACT Collaborators mission is to transform the delivery, quality, and outcomes of care provided to PLWD and their caregivers. In support of that mission, the Collaboratory funds one-year pilot studies for AD/ADRD-specific ePCTs of non-drug interventions embedded in healthcare systems. Because this is an emerging field, applicants selected to the pilot program are connected by the IMPACT Collaboratory Navigation team to subject matter experts in various domains of dementia clinical trials from across ten Cores and Teams who mentor investigators in refining and optimizing their pragmatic trial design. The Stakeholder Engagement Team (SET) is one such teams and is comprised of a team leader, associate team leader, and five executive committee members, including a PLWD. The SET works with applicants to improve the quality of ePCTs supported by the IMPACT Collaboratory in a variety of ways including: identifying research priorities from multiple stakeholder perspectives, assuring proposed interventions are relevant to stakeholder priorities, assessing feasibility of interventions, integration into everyday workflows, adaptation of interventions for site-specific contexts, and costs of adopting successful interventions into standard care.

In our review of applications to the pilot program, the SET uses applicable components of two guiding tools. First, to assess the strength of proposals across relevant stakeholder engagement domains, the SET uses the Readiness Assessment for Pragmatic Trials (RAPT)²⁷ model to evaluate key domains for stakeholders, such as alignment and cost. The RAPT is a set of formal criteria to assess the whether a non-drug intervention with established efficacy from a conventional study is ready for testing as a pragmatic trial. Developed as a guidance tool for researchers following a workshop convened by the National Institute on Aging as part of their 2017 National Research Summit¹⁸ on dementia care, the model can be used by research teams to assess an intervention’s readiness for a pragmatic trial across nine domains, including feasibility to implement, cost for healthcare systems, acceptability to providers, and alignment with stakeholder priorities. Each domain is scored with the results summarized graphically to visually highlight domains that contribute or detract from an intervention’s readiness.

The SET also advises investigators to consider how relevant the primary outcome of the intervention is to stakeholders, a reflective exercise that influences study design choices and aligns with the SET’s objective to convene a Lived Experience Panel in partnership with the Patient and Caregiver Reported Outcomes Core (PCRO) and the Alzheimer’s Association. The aim of the Lived Experience Panel is to engage participants, comprised of PLWD, family caregivers, and representatives of people living with moderate-to-severe dementia in developing patient-centered outcomes. This activity is intended to further ground Collaboratory activities in the voices of what matters most to PLWD and their caregivers.

The IMPACT Collaboratory reflects the increasing prominence of engagement in research, with formation of the SET team at the initiation of the Collaboratory as well as a multi-Stakeholder Advisory Committee. The SET is responsible for convening and synthesizing recommendations to the IMPACT Collaboratory from the Stakeholder Advisory Committee. The Committee is comprised of representatives from multiple stakeholder groups, including PLWD, caregivers, clinicians, healthcare system leaders, advocacy groups, policy makers, and payors with the purpose of advising the Collaboratory on stakeholder engagement activities, strategies to assist investigators with stakeholder engagement, and priority topics for the development of guidance materials from varied stakeholder perspectives.

In collaboration with the SAC, an objective of the SET was to define relevant stakeholder groups. As summarized in Figure 1, ePCTs in AD/ADRD require engagement with a wide range of stakeholders given the variety and complexity of clinical settings and care teams for PLWD. In addition to defining stakeholder groups, it was important to develop a process model for stakeholder engagement in the Collaboratory given the diversity of engagement-related roles and objectives (and an engagement model for the Collaboratory (see Figure 1). The model reflects the importance of stakeholder engagement at both a “macro” level (i.e. knowledge generation, development of recommendations and guidance through collaboration among the SET, SAC, Lived Experience Panel and other Collaboratory Cores) and a “micro” level (i.e. appropriate stakeholder engagement in funded pilot projects).

Figure 1:

Infographic Depicting Stakeholder Engagement in NIA IMPACT Collaboratory

Another goal of the SET is to develop a logic model and approach for evaluating stakeholder engagement in the pilot projects, building on the engagement factors detailed in the bottom right quadrant of the process model. Specifying proposed or hypothesized outcomes enables development of evaluation questions and metrics to guide collection of information about the impact of engagement. Pilot project awardees will report information on, for example, how they engaged PLWD and caregivers in refining the intervention, and any changes that were made based on their input. By establishing an evaluation plan, questions about effective elements of engagement can be addressed as the evidence accumulates, along with information about best practices, for improving engagement over time.

Based on recommendations from the SAC, the IMPACT Collaboratory will focus its engagement efforts on three objectives for guiding investigators as summarized in Table 1. First, we will leverage previous efforts and engage multiple stakeholder groups in topic generation to generate a list of high priority topics for ePCTs in AD/ADRD. Second, we will develop and disseminate guidance and training materials on ways to engage stakeholders in modifying components of evidence-based interventions to be more feasible in real-world settings and in ways that optimize buy-in. Third, we will engage these groups in identifying meaningful primary outcomes for ePCTs through the Lived Experience Panel. That is, if an intervention is successful during trial, what do PLWD, caregivers, healthcare systems and others want to obtain or change as a result? Aligning design and outcomes with what matters most to stakeholders is critical to the success of ePCTs. A lack of relevancy between the interventions selected by researchers and stakeholders’ everyday lives has been described as one reason why some interventions don’t get adopted, despite their apparent success during trial.²⁷ This can be avoided with robust stakeholder engagement early and often.

Discussion

Although most models of stakeholder engagement in research emphasize inclusion of multiple stakeholder groups throughout the life cycle of a study, there are unique complexities in both ePCTs and AD/ADRD populations. Partnerships with healthcare systems are essential to ePCTs, as is the need to include direct care staff in the inception, adaptation, and implementation phases of a project to ensure relevancy and feasibility. Engaging PLWD must be approached with sensitivity towards symptom progression, consent for participation, respect for privacy, and the potential for stigma. Opportunities for transactional and sustained engagement should be considered as should ways to engage stakeholders without placing burden on PLWD, family caregivers, direct care staff, providers, and the healthcare systems where ePCTs are embedded.^28-29 To that end, the IMPACT Collaborator has created a robust infrastructure to support stakeholder engagement.