Abstract:
The IMPACT Collaboratory is a national infrastructure and resource dedicated to transforming dementia care in real-world environments for millions of Americans and their care partners, using embedded pragmatic clinical trials. This new approach of applied clinical research holds the promise of accelerating the science of dementia care, improving relevancy of interventions to real-world partners, promoting health equity, and closing the gaps between research, everyday clinical practice, and lived experiences of people living with dementia and their care partners.
Keywords:
Alzheimer’s disease, dementia, pragmatic clinical trials, real-world
According to the Alzheimer’s Association (2023), more than 5.8 million Americans live with Alzheimer’s disease or an Alzheimer’s disease–related dementia (AD/ADRD), a group of irreversible and progressive brain disorders that destroy a person’s memory, language, and cognitive skills. By 2050, that number is expected to grow to 13 million. The lack of advances in interventions providing meaningful therapeutic benefit for AD/ADRD (Anderson et al., 2017; Livingston et al., 2020) have magnified a looming public health crisis. Despite spending an estimated $42 billion over the last quarter century to develop drugs that prevent, treat, and cure the disease, only a handful have been approved by the FDA to treat symptoms of AD/ADRD (Alzheimer’s Association, 2023; Cummings et al., 2014, 2022). Just as with detection and diagnosis, the use of emerging costly new drugs for Alzheimer’s disease will be mired in well-known health disparities and perpetuate health inequities (Quinones et al., 2020). Even if those entrenched problems were addressed, we cannot drug our way out of the Alzheimer’s epidemic (Karlawish, 2023).
Development of non-pharmacological interventions for AD/ADRD, which target critically challenging aspects of the disease not amenable to pharmacological approaches (e.g., health services delivery, care partner [CP] support, goal-directed care; Watt et al., 2019) has also faced challenges. Two systematic reviews evaluating the strength of the evidence, one by the Agency for Healthcare Research and Quality (Minnesota Evidence-based Practice Center, 2020) and the other by the National Academies of Sciences, Engineering, and Medicine (Larson & Stroud, 2021), described the pipeline of non-drug dementia care interventions targeting people living with dementia (PLWD) and their CPs as extremely limited, with only two interventions ready for testing in real-world settings.
When it comes to improving dementia care, however, experts stress that drug and non-drug interventions should not be used in isolation. Dementia prevention, intervention, and care require holistic multicomponent interventions that address physical and mental health, social care, support, and management of neuropsychiatric symptoms so that PLWD and their CPs can live as well as possible (Livingston et al., 2020). Put simply, we need more research on what kind of dementia care works, how, and for whom, to make a difference in the real world.
Timely realization of the benefits of AD/ADRD research is paramount given the magnitude of this public health crisis. However, there are known to be difficulties getting research evidence integrated into everyday clinical practice, a process that reportedly takes 17 years (Morris et al., 2011). This lag time is, undoubtedly, much too long for the millions of Americans suffering with AD/ADRD, their CPs, and the healthcare systems (HCS) that provide dementia care. Scalable and adoptable interventions that are effective in improving the care delivered to this vulnerable population are desperately needed. Meeting this challenge demands innovative approaches and robust infrastructures that bring together HCS, researchers, community partners, funders, and regulators focused on a common purpose to do dementia research differently.
Coordinated Efforts for New Approaches and Solutions
Driven by major initiatives (Mitchell et al., 2020; Office of the Assistant Secretary for Planning and Evaluation [OASPE], 2018) from Congress and the National Institutes of Health (NIH), embedded pragmatic clinical trials (ePCTs) provide new approaches and solutions to closing the critical gap between research and practice through a multifaceted national strategy of rethinking clinical trials. ePCTs are conducted in real-world environments, such as healthcare systems and clinical settings, with the goal of quickly and efficiently generating high-quality evidence to inform clinical and policy-level decisions (Mitchell et al., 2020; NIH PTC, 2024).
In 2012, the NIH Pragmatic Trials Collaboratory (https://rethinkingclinicaltrials.org) was founded to strengthen the nation’s capacity to conduct ePCTs on major public health issues by engaging healthcare delivery organizations as research partners. Building on this foundational infrastructure and lessons learned from a 2017 National Institute on Aging (NIA) conference titled, “State of the Science for Pragmatic Trials of Non-Pharmacological Interventions for Persons with Dementia” (OASPE, 2018), the NIA launched a national competition for a dementia-focused pragmatic trials research incubator focused specifically on non-pharmacological interventions to improve dementia care targeting the unique needs of PLWD and their CPs.
‘ePCTs test if and how interventions work when conducted in everyday healthcare settings under real-world conditions.’
The outcome was a cooperative agreement (U54) of the National Institute on Aging (NIA) Imbedded Pragmatic Alzheimer's disease (AD) and AD-Related Dementias (AD/AD/ADRD) Clinical Trials (IMPACT) Collaboratory (Mitchell et al., 2020). The mission of IMPACT is to build the nation’s capacity to conduct ePCTs for PLWD and their CPs.
Defining ePCTs
Unlike traditional clinical trials that test if and how interventions work under ideal conditions in well-controlled environments among relatively homogeneous populations, ePCTs test if and how interventions work when conducted in everyday healthcare settings under real-world conditions. Pragmatic clinical trials (PCTs) are “designed for the primary purpose of informing decision-makers regarding the comparative balance of benefits, burdens and risks of a biomedical or behavioral health intervention at the individual or population level” (Califf & Sugarman, 2015).
What makes a PCT an ePCT is that the research is embedded in settings where people already receive their usual clinical care with the aim of accelerating the pace at which healthcare systems adopt evidence into everyday clinical practice. There are many benefits to ePCTs, such as leveraging existing administrative or electronic health records to identify participants and ascertain outcomes, expanding eligibility criteria and recruitment, randomizing at the unit of care or setting level rather than the individual level, and potentially lower costs (Mitchell et al., 2020).
Challenges of ePCTs include maintaining the rigor of a clinical trial in busy clinical care settings that may have competing priorities, staff turnover, and unique regulatory considerations (Mitchell et al., 2020). ePCTs are an emerging field that have the potential to transform the landscape of applied research in aging across a variety of topics and close the gap between the traditionally siloed worlds of research and the real-world. Next, we describe how ePCTs are being used to address the national public health priority area of AD/ADRD.
ePCTs for Dementia Care
Because studies show that PLWD are at high risk of receiving uncoordinated, low-quality, high-cost care, ultimately leading to poor health outcomes and quality of life, there is an urgent need to generate a high-quality equitable evidence base about what type of dementia care works (Mitchell et al., 2020; OASPE, 2018). This type of applied clinical research holds promise to accelerate the science of dementia care, improve the relevance of interventions to real-world partners, and close the gaps between research, everyday clinical practice, and lived experiences of people with AD/ADRD and their CPs.
Despite the promise of this developing field of ePCTs in AD/ADRD, it also has challenges. For example, as a consequence of embedding PCTs in everyday clinical care, scientific studies are conducted in messy real-world environments (Tuzzio et al., 2019). Operational realities and stressors include competing priorities, turnover and retention in personnel, buy-in by busy direct care staff, regulatory oversight, inspections, infection outbreaks, and many other factors. To maintain the rigor of science under real-world conditions, researchers must develop new competencies to create compelling value propositions for HCS (NIA IMPACT Collaboratory, 2021), address priority areas for PLWD and their CPs, maximize intervention implementation in the context of clinical care (Tuzzio et al., 2020), and leverage administrative health data to identify trial participants and track their outcomes (Hanson et al., 2020). IMPACT’s resources are put toward building those competencies by funding research, training investigators (NIA IMPACT Collaboratory 2024), building a knowledge-base (NIA IMPACT Collaboratory, n.d.), and engaging partners (Harrison et al., 2020).
Integrating Health Equity
It is well known that persons from minoritized groups—including those defined by racial, ethnic, sexual, gender, socioeconomic, as well as geographic factors—are vastly underrepresented in traditional randomized clinical trials, despite experiencing higher rates of dementia and worse health outcomes relative to non-Hispanic White populations (Cooper et al., 2010; Matthew et al., 2019; Mayeda et al., 2016). As a result, evidence about the efficacy and effectiveness of dementia interventions, accrued over decades, may not be applicable or relevant to diverse, minoritized populations, making our baseline knowledge skewed and inequitable.
As a new approach to applied research, ePCTs aim to disrupt the perpetuation of inequality in the design and conduct of research to improve care for PLWD and their CPs. From the outset, integrating health equity into every aspect in the design and conduct of ePCTs, including representation, relevancy, and partnership with people from marginalized and minoritized groups that are disproportionately impacted by AD/ADRD, has been paramount in the knowledge-building and advancing methodology activities of the IMPACT Collaboratory (Quinones et al., 2020).
Including Voices of Lived Experience(s)
Because ePCTs have been defined as an essential new approach in the national strategy for AD/ADRD to rapidly and dramatically improve dementia care, it is essential that the research is aligned with what matters most to PLWD, their CPs, direct care staff, and the HCS that care for them (Bennett et al., 2022; Largent et al., 2022). A lack of connection between the interventions selected by researchers for testing and their relevancy to the priorities of PLWD and their CPs may explain, in part, their lack of uptake by HCS in clinical care (Baier et al., 2019).
‘ePCTs aim to disrupt the perpetuation of inequality in the design and conduct of research to improve care for PLWD and their CPs.’
To avoid this known pitfall, IMPACT took a more activist approach to engaging community partners, reflected in the unique Lived Experience Panel, established in collaboration with the Alzheimer’s Association. This panel is a diverse group of 14 PLWD and CPs who advise IMPACT on its research direction. The panel intentionally includes voices and perspectives of PLWD and CPs, recognizing that they share a common experience of living with AD/ADRD, but have diverse lived experiences that must be understood to make the science equitable, meaningful, and salient.
In addition to traditional scientific peer review of applications to its pilot study funding mechanism, IMPACT also engages PLWD and CPs in a lived experience review panel to evaluate pilot study proposals based on the following three questions: Is this research important? Does this research address an unmet need? Will this make a difference in the real world? Feedback from these diverse partners is integrated into funding decisions.
Advancing Applied Research in Aging
The recognition that conducting ePCTs with PLWD and their CPs merited a focused and coordinated initiative, combined with momentum and foundational work laid by the NIH Pragmatic Trials Collaboratory and others, have created conditions to advance the field and for the IMPACT Collaboratory to emerge and flourish. Advancing ePCTs as a new approach and solution to transform the real-world delivery and outcomes of care provided to Americans living with dementia cannot be realized without devoting attention and training resources to designing and conducting trials in real-world environments, holistically integrating health equity, and including diverse perspectives from community partners early and often. The IMPACT Collaboratory is a national infrastructure and resource that is making deliberate strides toward these audacious, and much needed, goals to improve dementia care in real-world environments for millions of Americans and their care partners.
This work was supported by the National Institute of Aging (NIA) of the National Institutes of Health under Award Number U54AG063546, which funds NIA Imbedded Pragmatic Alzheimer’s Disease and AD-Related Dementias Clinical Trials Collaboratory (NIA IMPACT Collaboratory).
Sponsor’s Role: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Jill Harrison, PhD, is an executive director of the NIA IMPACT Collaboratory and associate professor of the Practice at Brown University, School of Public Health in Providence, RI. She may be contacted at jill_s_harrison@brown.edu. Susan L. Mitchell, MD, MPH, is a principal investigator of the NIA IMPACT Collaboratory, a senior scientist at the Marcus Institute for Aging Research, Hebrew SeniorLife, and a professor of Medicine at Harvard Medical School in Cambridge, MA. Vincent Mor, PhD, is a principal investigator of the NIA IMPACT Collaboratory, and a professor at Brown University, School of Public Health. Ellen P. McCarthy, PhD, MPH, is an executive director of the NIA IMPACT Collaboratory and an associate scientist in Palliative Care at the Hinda and Arthur Marcus Institute for Aging Research and an associate professor of Medicine at Harvard Medical School and Epidemiology at the T.H. Chan Harvard School of Public Health.
Photo credit: Shutterstock/Ina Raschke
References
Alzheimer's Association. (2023). 2023 Alzheimer's disease facts and figures. Alzheimer’s & Dementia, 19, 1598–1695. https://doi.org/10.1002/alz.13016
Anderson, R. M., Hadjichrysanthou, C., Evans, S., & Wong, M. M. (2017). Why do so many clinical trials of therapies for Alzheimer's disease fail? The Lancet, 390(10110), 23272329. https://doi.org/10.1016/S0140-6736(17)32399-1
Baier, R. R., Jutkowitz, E., Mitchell, S. L., McCreedy, E., & Mor, V. (2019). Readiness assessment for pragmatic trials (RAPT): a model to assess the readiness of an intervention for testing in a pragmatic trial. BMC Medical Research Methodology, 19(1), 156. https://doi.org/10.1186/s12874-019-0794-9
Bennett, A. V., Hanson, L. C., Epstein-Lubow, G., & Zimmerman, S. I. (2022, August 18). 2021-2022 lived experience panel report: Priorities for person and caregiver relevant outcomes in dementia intervention research. NIA IMPACT Collaboratory. https://doi.org/10.58234/82222234
Califf, R. M., & Sugarman J. (2015). Exploring the ethical and regulatory issues in pragmatic clinical trials. Clinical Trials, 12(5): 436–441. https://doi.org/10.1177/1740774515598334
Cooper, C., Tandy, A. R., Balamurali, T. B., & Livingston, G. (2010). A systematic review and meta-analysis of ethnic differences in use of dementia treatment, care, and research. American Journal of Geriatric Psychiatry, 18(3), 193–203. https://doi.org/10.1097/JGP.0b013e3181bf9caf
Cummings, J. L., Goldman, D. P., Simmons-Stern, N. R., & Ponton, E. (2022). The costs of developing treatments for Alzheimer's disease: A retrospective exploration. Alzheimer’s & Dementia, 18(3), 469–477. https://doi.org/10.1002/alz.12450
Cummings, J. L., Morstorf, T., & Zhong, K. (2014). Alzheimer's disease drug-development pipeline: Few candidates, frequent failures. Alzheimer’s Research & Therapy, 6(4), 37. https://doi.org/10.1186/alzrt269
Hanson, L. C., Bennett, A. V., Jonsson, M., Kelley, A., Ritchie, C., Saliba, D., Teno, J., & Zimmerman, S. (2020). Selecting outcomes to ensure pragmatic trials are relevant to people living with dementia. Journal of the American Geriatrics Society, 68(Suppl 2), S55–S61. https://doi.org/10.1111/jgs.16619
Harrison, J., Maslow, K., Tambor, E., Phillips, L., Frank, L., Herndon, L., & Epstein-Lubow, G. (2020). Engaging stakeholders in the design and conduct of embedded pragmatic clinical trials for Alzheimer's disease and Alzheimer's disease–related dementias. Journal of the American Geriatrics Society, 68(Suppl 2), S62–S67. https://doi.org/10.1111/jgs.16630
Karlawish, J. (2023). The problem of Alzheimer's: How science, culture, and politics turned a rare disease into a crisis and what we can do about it (1st ed.). St. Martin's Press.
Largent, E., Karlawish, J., Joffe, S., Epstein-Lubow, G. (2022). 2021-2022 lived experience panel report: Ethical challenges in conducting research using a waiver of informed consent with people living with dementia. NIA IMPACT Collaboratory. https://doi.org/10.58234/92591162
Larson, E. B., & Stroud, C. (Eds.). (2021). (2021). Meeting the challenge of caring for persons living with dementia and their care partners and caregivers: A way forward. National Academies of Sciences, Engineering, and Medicine.
Livingston, G., Huntley, J., Sommerlad, A., Ames, D., Ballard, C., Banerjee, S., Brayne, C., Burns, A., Cohen-Mansfield, J., Cooper, C., Costafreda, S. g., Dias, A., Fox, N., Gitlin, L. N., Howard, R., Kales, H. C., Kivimäki, M., Larson, E. B., Ogunniyi, A.,… Mukadam, N. (2020). Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. The Lancet, 396(10248), 413–446. https://doi.org/10.1016/S0140-6736(20)30367-6
Matthews, K. A., Xu, W., Gaglioti, A. H., Holt, J. B., Croft, J. B., Mack, D., & McGuire, L. C. (2019). Racial and ethnic estimates of Alzheimer's disease and related dementias in the United States (2015–2060) in adults aged ≥65 years. Alzheimer's & Dementia Journal, 15(1), 17–24. https://doi.org/10.1016/j.jalz.2018.06.3063
Mayeda, E. R., Glymour, M. M., Quesenberry, C. P., & Whitmer, R. A. (2016). Inequalities in dementia incidence between six racial and ethnic groups over 14 years. Alzheimer's & Dementia Journal, 12(3), 216–224. https://doi.org/10.1016/j.jalz.2015.12.007
Minnesota Evidence-based Practice Center. (2020). Care interventions for people living with dementia and their caregivers. Report to the Agency for Healthcare Research and Quality, United States Department of Health and Human Services. https://effectivehealthcare.ahrq.gov/sites/default/files/pdf/cer-231-dementia-interventions-final_0.pdf
Mitchell, S. L., Mor, V., Harrison, J., & McCarthy, E. P. (2020). Embedded pragmatic trials in dementia care: Realizing the cision of the NIA IMPACT Collaboratory. Journal of the American Geriatrics Society, 68(Suppl 2), S1–S7. https://doi.org/10.1111/jgs.16621
Morris, Z. S., Wooding, S., & Grant, J. (2011). The answer is 17 years, what is the question: Understanding time lags in translational research. Journal of the Royal Society of Medicine, 104(12), 510–520. https://doi.org/10.1258/jrsm.2011.110180
National Institute on Aging IMPACT Collaboratory. (n.d.). IMPACT knowledge repository. https://dcricollab.dcri.duke.edu/sites/impact/Pages/search.aspx
National Institute on Aging IMPACT Collaboratory. (2021). Creating effective value propositions: Engaging key stakeholders in embedded pragmatic clinical trials (ePCTs) to evaluate evidence based programs in dementia care. https://impactcollaboratory.org/new-guidance-document-offers-steps-for-creating-a-value-proposition/
National Institute on Aging IMPACT Collaboratory. (2024). Certificate program: Best practices for integrating health equity into embedded pragmatic clinical trials for dementia care [Video training curriculum]. https://impactcollaboratory.org/health-equity-certificate-program/
Office of the Assistant Secretary for Planning and Evaluation. (2018). National research summit on care, services and supports for persons with dementia and their caregivers: Final summit report. United States Department of Health and Human Services. https://aspe.hhs.gov/reports/national-research-summit-care-services-supports-persons-dementia-their-caregivers-final-summit
Quinones, A. R., Mitchell, S. L., Jackson, J. D., Aranda, M. P., Dilworth-Anderson, P., McCarthy, E. P., & Hinton, L. (2020). Achieving health equity in embedded pragmatic trials for people living with dementia and their family caregivers. Journal of the American Geriatrics Society, 68(Suppl 2), S8–S13. https://doi.org/10.1111/jgs.16614
Tuzzio, L., Hanson, L. R., Reuben, D. B., Baier, R. R., Gurwitz, J. H., Bayliss, E. A., Williamson, J., Fraser, J. R., Sherman, S. J., & Larson, E. B. (2020). Transforming Dementia care through pragmatic clinical trials embedded in learning healthcare systems. Journal of the American Geriatrics Society, 68(Suppl 2), S43–S48. https://doi.org/10.1111/jgs.16629
Tuzzio, L., Larson, E. B., Chambers, D. A., Coronado, G. D., Curtis, L. H., Weber, W. J., Zatzick, D. F., & Meyers, C. M. (2019). Pragmatic clinical trials offer unique opportunities for disseminating, implementing, and sustaining evidence-based practices into clinical care: Proceedings of a workshop. Healthcare, 7(1), 51—57. https://doi.org/10.1016/j.hjdsi.2018.12.003
Watt, J. A., Goodarzi, Z., Veroniki, A. A., Nincic, V., Khan, P. A., Ghassemi, M., Thompson, Y., Tricco, A. C., & Straus, S. E. (2019). Comparative efficacy of interventions for aggressive and agitated behaviors in dementia: A systematic review and network meta-analysis. Annals of Internal Medicine, 171(9), 633–642. https://doi.org/10.7326/M19-0993
