A Global Public Health Crisis
Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD) refer to a group of irreversible and progressive brain disorders that destroy a person’s memory and thinking skills. Often described as a global epidemic, currently more than 50 million people world-wide live with AD/ADRD. By 2050, that number is expected to rise to more than 145 million people globally, overwhelming existing healthcare systems. At the same time, advances in Alzheimer’s disease are disproportionate to the scale of the problem. According to the CDC, despite declines in deaths among other common diseases, such as cancers, heart disease, stroke, and HIV, deaths from AD increased by 55% from 1999 to 2014 in every race, sex, and ethnicity category. In the United States, Alzheimer’s disease remains the sixth leading cause of death.
So far, only a handful of prescription drugs have been approved to treat Alzheimer’s disease. Because the majority of drug trials for AD fail, the rate at which people develop AD significantly outpaces pharmacologic advances in prevention, symptom management, and curative treatments. As, Jason Karlawish, MD, has said, “We’re not going to drug our way out’ of Alzheimer’s disease.” With the magnitude of this public health crisis bearing down on us, accepting the reality that a pharmacological solution is unlikely in the near term can be, as they say, a hard pill to swallow. However, we are not without hope. Healthcare systems and researchers are renewing their focus on the promise of non-pharmacological approaches to care for people living with dementia (PLWD) and their caregivers. Non-drug interventions have therapeutic benefit in their own right and can, in some instances, be more effective than drug-interventions for treating certain symptoms of dementia.
A Promising New Strategy
The good news is that the National Institutes of Health (NIH) is focusing on AD/ADRD research with specific emphasis on embedded pragmatic clinical trials (ePCTs) as part of a multi-faceted national strategy of rethinking clinical trials. The intention is to purposefully connect what have traditionally been two separate worlds, scientific research and everyday clinical practice, in order to accelerate progress in treating AD/ADRD and by improving the relevancy of trials and accelerating the uptake of research findings by end-users. Because studies show that people living with dementia are at high risk of receiving uncoordinated and poor-quality care, ultimately leading to adverse health outcomes, poor quality of life, and misuse of resources, there is an urgent need to conduct pragmatic trials embedded in health care systems to generate a high-quality evidence base about care that works.
The NIA IMPACT Collaboratory
In order to meet the urgent public health need for delivering high quality, evidence-based care to people living with dementia, and to their care givers, The National Institute on Aging (NIA) IMbedded Pragmatic Alzheimer’s Disease (AD) and AD-Related Dementias (AD/ADRD) Clinical Trials (IMPACT) Collaboratory was established in mid-2019. The mission of the Collaboratory is to build the nation’s capacity to conduct pragmatic clinical trials of interventions embedded within health care systems for people living with dementia and for their caregivers.
Benefits and Challenges of ePCTs in AD/ADRD
Contrary to traditional clinical trials that typically test if and how interventions work among relatively homogeneous populations under ideal conditions in well-controlled environments, ePCTs are designed to inform clinical and policy-level decisions by testing whether an intervention actually works when it is embedded into everyday healthcare settings under real-world conditions. Some benefits of ePCTs include having fewer exclusion criteria for participants, the ability to cluster randomize at the site level, being less expensive, and accelerating the rate at which health care systems adopt evidence into practice. Of course, ePCTs also have their own challenges and limitations. For example, ePCTs need to maintain the rigors of scientific study while at the same time navigating the messiness of everyday care settings, such as buy-in of leadership and direct-care staff, stressors of productivity and volume, regulatory oversight, issues of staff turnover and retention, and competing priorities for staff members charged with delivering the intervention, among many others. ePCTs with PLWD in health care settings, such as nursing homes, may encounter additional challenges in the conduct of embedded research, such as unique regulatory considerations for involving vulnerable populations in research, limitations of using healthcare system data to identify PLWD and measure outcomes, as well as site-specific challenges that influence fidelity to the research methodology and overall implementation of the intervention.
Recognizing an Embedded Pragmatic Trial when we see it
While there is large agreement around the definition of a traditional RCT, including its hallmark characteristics, there is significantly less agreement about what constitutes an ePCT. These competing perspectives and confusion are not without cause. ePCTs bridge traditionally siloed worlds of clinical research and day-to-day care delivery. While a defining characteristic of ePCTs is that they are embedded in health care systems, that embeddedness is necessary, but not sufficient, in helping us to recognize an ePCT when we see it.
ePCTs exist within a complex ecosystem of multiple stakeholders, including people with dementia, caregivers, researchers, providers, payers, health care system leaders, and direct-care staff. While ideally, these stakeholders would engage because of the shared relevancy and common goals associated with a research project, the reality is that the majority of trial research is often generated by researchers-alone and permission to embed a research study within a health care system can be granted by leaders that may be unaware of the complexities associated with modifying existing routines and the feasibility of an already fully employed staff to deliver an intervention in their existing workload. To overcome these challenges, learning health systems are adopting strategies to co-design research and care delivery, but this is still far from the norm.
The key point is that, while promising, ePCTs require researchers and health care systems to partner in unique and sometimes unanticipated ways. An effective ePCT cannot be a retrofit of a rigorous clinical study into entrenched organizational cultures, systems, and workflows. Rather, in order to meet the needs of a health system partner, a researcher will have to balance rigor with feasibility. The needs of multi-stakeholder groups involved in the design and conduct of ePCTs may be conflicting and require varying degrees and kinds of compromises that can be difficult to standardize. Because this give and take can be both site and project specific, head-to-head comparisons of designs and comparing outcomes across studies is more challenging than in traditional research.
Guidance for Researchers
While the definition of an ePCT remains somewhat of a moving target, guidance for researchers interested in ePCTs is becoming more available. As part of the National Institute on Aging Research Summit on Dementia Care in 2017, the Readiness Assessment for Pragmatic Trials (RAPT) model was developed as a tool for researchers to determine whether an intervention is ready for a pragmatic clinical trial. The model can be used by research teams to assess an intervention’s readiness for a pragmatic trial across nine domains, such as evidence, risk, feasibility, and cost. The PRECIS-2 tool provides guidance to help trialists make design choices that move their trial along a pragmatic/explanatory continuum. Both tools are increasingly becoming industry standards.
Additionally, the new NIA IMPACT Collaboratory is already actively engaged in building investigator capacity through training and knowledge generation by developing and disseminating best practices through podcasts, grand rounds, post-doctoral fellowships, career development awards, funding and guiding pilot ePCTs and providing the methodological and technical support needed to transform pilot studies into full-scale ePCTs.
This work was funded 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). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
To learn more about the IMPACT Collaboratory visit www.impactcollaboratory.org.