The crisis in recruitment for clinical trials in Alzheimer's and dementia: An action plan for solutions

The purpose of this editorial is to articulate the framework for a strategy to overcome the crisis in participant enrollment, a problem that is poised to derail the first goal of the National Plan to Address Alzheimer's Disease—to prevent and effectively treat Alzheimer's disease by 2025. The first goal of the National Plan to Address Alzheimer's Disease (hereinafter, the Plan) is to prevent and effectively treat Alzheimer's disease by 2025. The development of interventions to delay the onset, or slow or halt the progress, of dementia remains the overarching strategy toward achieving this goal. Now the crucial question is how to accelerate the overall enterprise of therapy development, in alignment with this goal, to avert the economic and social havoc that will occur as ever-growing numbers of people develop dementia. The formulation and launch of various efforts to improve current paradigms of treatment discovery and development that will alter the progression of disease process is a high-priority challenge for the Plan, policy makers, and the scientific community at large. the identification of safe and effective drugs well-controlled and well-powered pivotal clinical trials recruitment of a large number of research participants for clinical trials Although it is feasible that additional funding will address the first two factors, it will not necessarily address the third and most important barrier to therapy development, participant recruitment. In fact, the substantial increases in research funding will likely further expand the need for already limited research participants. The challenges associated with current models of research and development for the treatment and prevention of dementia, and the question of how to improve the productivity of these efforts, have been extensively deliberated at several meetings organized by the Alzheimer's Association's Research Roundtable, the Alzheimer's Association International Conference, Clinical Trials on Alzheimer's Disease, the Advances in Alzheimer Therapy conferences, and the EU-US Task Force 1-7. These deliberations have examined contributors to the challenges, as well as potential solutions to the problems facing current therapy development efforts. Although much progress has been made in improving the efficiency of clinical research in dementia, for example by using genetic or biomarker screening for sample enrichment 8, one factor has not been adequately addressed: difficulty in recruiting study participants. Second only to lack of adequate research funding, difficulty in participant recruitment is perhaps the most significant major barrier to clinical research progress. Difficulty in participant recruitment is a major reason for both lengthening the duration of clinical trials and increasing their costs, thus reducing efficiency. The struggle to enroll participants is a long-standing problem, dating back at least to the mid-1990s 9, and is a widespread difficulty for most dementia clinical trials and longitudinal studies 10-13. This challenge will increase dramatically in the coming years. One of the unique problems facing the field is that few people with Alzheimer's or another dementing illness participate in clinical trials. There are a variety of reasons for this. First, few are eligible; only approximately 20% to 25% of people with Alzheimer's are eligible to participate in Alzheimer's trials 14. In addition, few are referred by their physicians to clinical trials, due to poor physician awareness, fatalism, loss of patient to trial, or geographic distance. Another important contributing factor is that many clinical trials in Alzheimer's and dementia are now seeking participants who are in either the prodromal or asymptomatic phases of disease 15. In 2011, the National Institute on Aging (NIA) and the Alzheimer's Association released new research guidelines for diagnostic criteria. These guidelines take into account the recognition that Alzheimer's disease is a process that develops over decades, with neuropathological events occurring many years before measurable symptoms appear, let alone become advanced enough to be considered dementia. In accordance with this understanding of the disease process, many new clinical trials are using genetic risk factors and biomarkers (particularly amyloid positron emission tomography imaging) to identify individuals at elevated risk for participation. Included among these are the Anti-Amyloid Treatment in Asymptomatic Alzheimer's study, the TOMMORROW trial, the Autosomal Dominant Alzheimer's Disease trial, the Generations study, and the Dominantly Inherited Alzheimer Network Trials Unit. Such trials have tremendous potential to slow or potentially even arrest the progress of the disease before it reaches the dementia stage. However, they present their own unique challenges for recruitment, as typically people in these early phases of the disease are unaware of their situation and are not treatment seeking. In other words, these studies rely on recruiting healthy individuals to participate in trials of experimental medications. Given the likelihood that treatments intended to affect the fundamental causes of the disease will likely be most effective when begun early, such trials are likely to proliferate in the near future, further exacerbating the recruitment crisis. A group of key stakeholders (listed below) met on July 24, 2016, in Toronto, Canada, in conjunction with AAIC, to discuss this problem and a potential solution. The group consisted of experts from academia, industry, government, and the nonprofit sector. The first component of the proposed action plan is to address the immediate and urgent needs of ongoing clinical studies, led and funded by NIA, the Alzheimer's Association, and other key stakeholders. This near-term strategy calls for the launch of a major national media campaign designed to increase public awareness regarding the critical need for volunteers as participants for clinical studies, including healthy individuals for prevention studies. A draft proposal for such an initiative is being circulated among the research community (see supplemental material). The second component of the proposed action plan is designed to formulate long-term strategic solutions to the dilemma resulting from the growing difficulties in recruiting participants. This part of the plan calls for the Alzheimer's Association, along with other key stakeholders, to convene a “Workgroup on Clinical Research Resources and Infrastructure,” which would consider a set of options to address this problem. One example for a long-term solution the workgroup might study is the concept of a National Core designed as a multiuser resource to serve the needs of clinical trials and longitudinal observational studies seeking to recruit participants. This model of a shared research resource has been used, in various forms, as an integral part of several funding mechanism by the NIH and others. For example, cores are often an essential component in such NIH funding mechanisms as Program Projects and Centers. The concept of a core facility has also been used as a stand-alone research resource for the purposes of collecting, banking, and distributing other research resources, such as for cells, tissue, and other biofluids. This and other models should be studied, and a suitable model should be selected. Address participant recruitment difficulties for clinical trials and longitudinal observational studies Specifically address recruitment of African-Americans, Latinos, and others who are currently under-represented in clinical trials Be submitted for review by the Advisory Council on Alzheimer's Research, Care, and Services Be suitable for implementation as part of the National Plan to Address Alzheimer's Disease Be designed to build upon both the Plan's Goal 1: Prevent and Effectively Treat Alzheimer's Disease by 2025, and Goal 4: Expand Public Awareness and Engagement The editors of Alzheimer's & Dementia and the Alzheimer's Association invite letters and brief comments regarding options for solutions to this global dilemma from the clinical research community. In the near future, the Alzheimer's Association and other key stakeholders will hold a public webinar (www.alz.org/recruitment_webinar) to solicit feedback on the ideas presented in this editorial. List of participants in the Toronto Meeting Paul Aisen University of Southern California Alzheimer's Therapeutic Research Institute Samantha Budd Haeberlein Biogen Maria C. Carrillo Alzheimer's Association Billy Dunn Food and Drug Administration Keith N. Fargo Alzheimer's Association Richard Hodes National Institute on Aging David Holtzman Department of Neurology, Washington University School of Medicine in St. Louis Harry Johns Alzheimer's Association Zaven Khachaturian Alzheimer's & Dementia: The Journal of the Alzheimer's Association Michael Krautkramer Eli Lilly and Company Eliezer Masliah National Institute on Aging David Michelson Merck Research Laboratories Gerald Novak Janssen Research and Development Creighton Phelps National Institute on Aging William Z. Potter National Institute of Mental Health Laurie Ryan National Institute on Aging Nina Silverberg National Institute on Aging George Vradenburg UsAgainstAlzheimer's & Global Alzheimer's Platform Foundation Michael W. Weiner Center for Imaging of Neurodegenerative Diseases, San Francisco VA Medical Center Supplementary data related to this article can be found at doi:https://doi.org/10.1016/j.jalz.2016.10.001. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.