Analysis of eligibility criteria in Alzheimer's and related dementias clinical trials.

Overly restrictive clinical trial eligibility criteria can reduce generalizability, slow enrollment, and disproportionately exclude historically underrepresented populations. The eligibility criteria for 196 Alzheimer's Disease and Related Dementias (AD/ADRD) trials funded by the National Institute on Aging were analyzed to identify common criteria and their potential to disproportionately exclude participants by race/ethnicity. The trials were categorized by type (48 Phase I/II pharmacological, 7 Phase III/IV pharmacological, 128 non-pharmacological, 7 diagnostic, and 6 neuropsychiatric) and target population (51 AD/ADRD, 58 Mild Cognitive Impairment, 25 at-risk, and 62 cognitively normal). Eligibility criteria were coded into the following categories: Medical, Neurologic, Psychiatric, and Procedural. A literature search was conducted to describe the prevalence of disparities for eligibility criteria for African Americans/Black (AA/B), Hispanic/Latino (H/L), American Indian/Alaska Native (AI/AN) and Native Hawaiian/Pacific Islander (NH/PI) populations. The trials had a median of 15 criteria. The most frequent criterion were age cutoffs (87% of trials), specified neurologic (65%), and psychiatric disorders (61%). Underrepresented groups could be disproportionately excluded by 16 eligibility categories; 42% of trials specified English-speakers only in their criteria. Most trials (82%) contain poorly operationalized criteria (i.e., criteria not well defined that can have multiple interpretations/means of implementation) and criteria that may reduce racial/ethnic enrollment diversity.

Recommendations to address key recruitment challenges of Alzheimer's disease clinical trials.

Clinical trials for Alzheimer's disease (AD) are slower to enroll study participants, take longer to complete, and are more expensive than trials in most other therapeutic areas. The recruitment and retention of a large number of qualified, diverse volunteers to participate in clinical research studies remain among the key barriers to the successful completion of AD clinical trials. An advisory panel of experts from academia, patient-advocacy organizations, philanthropy, non-profit, government, and industry convened in 2020 to assess the critical challenges facing recruitment in Alzheimer's clinical trials and develop a set of recommendations to overcome them. This paper briefly reviews existing challenges in AD clinical research and discusses the feasibility and implications of the panel's recommendations for actionable and inclusive solutions to accelerate the development of novel therapies for AD.

Facilitators, Challenges, and Messaging Strategies for Hispanic/Latino Populations Participating in Alzheimer's Disease and Related Dementias Clinical Research: A Literature Review.

Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD) disproportionally affect Hispanic and Latino populations, yet Hispanics/Latinos are substantially underrepresented in AD/ADRD clinical research. Diverse inclusion in trials is an ethical and scientific imperative, as underrepresentation reduces the ability to generalize study findings and treatments across populations most affected by a disease. This paper presents findings from a narrative literature review (N = 210) of the current landscape of Hispanic/Latino participation in clinical research, including the challenges, facilitators, and communication channels to conduct culturally appropriate outreach efforts to increase awareness and participation of Hispanics/Latinos in AD/ADRD clinical research studies. Many challenges identified were systemic in nature: lack of culturally relevant resources; staffing that does not represent participants' cultures/language; eligibility criteria that disproportionately excludes Hispanics/Latinos; and too few studies available in Hispanic/Latino communities. The paper also details facilitators and messaging strategies to improve engagement and interest among Hispanics/Latinos in AD/ADRD research, starting with approaches that recognize and address the heterogeneity of the Hispanic/Latino ethnicity, and then, tailor outreach activities and programs to address their diverse needs and circumstances. The needs identified in this article represent longstanding failures to improve engagement and interest among Hispanics/Latinos in AD/ADRD research; we discuss how the field can move forward learning from the experiences of the COVID-19 pandemic.

Transforming the Early Drug Development Paradigm at the National Cancer Institute: The Formation of NCI's Experimental Therapeutics Clinical Trials Network (ETCTN).

Early drug development for cancer requires broad collaboration and skilled clinical investigators to enable enrollment of patients whose tumors have defined molecular profiles. To respond to these challenges, the National Cancer Institute (NCI) transformed its 60-year-old early-phase drug development program in 2014 into the Experimental Therapeutics Clinical Trials Network (ETCTN). The ETCTN is a consolidated, national network of 40+ academic institutions responsible for conducting more than 100 early-phase clinical trials. It promotes team science coordinated among basic, translational, and clinical investigators, emphasizing the inclusion of early career trialists. This perspective provides a brief overview of the ETCTN, summarizes its successes and challenges over its first grant funding cycle, and discusses the program's future directions. Measures indicated strong connectivity across the institutions, significant increases in investigator approval of the ETCTN scientific portfolio from years 1 to 4, and substantial research activity over 5 years, with 334 letters of intent submitted, 102 trials activated, and 3,570 patients accrued. The ETCTN's successful adoption relied heavily on the inclusion of senior investigators who have long-standing interactions with the NCI and a willingness to participate in a team science approach and to mentor early career investigators. In addition, NCI invested substantial resources in a centralized infrastructure to conduct trials and to support the inclusion of biomarkers in its studies. The ETCTN provides evidence that a collaborative national clinical trial network for early drug development is feasible and can address the demands of precision medicine approaches to oncologic clinical trials.

Factors Affecting Combination Trial Success (FACTS): Investigator Survey Results on Early-Phase Combination Trials.

Experimental therapeutic oncology agents are often combined to circumvent tumor resistance to individual agents. However, most combination trials fail to demonstrate sufficient safety and efficacy to advance to a later phase. This study collected survey data on phase 1 combination therapy trials identified from ClinicalTrials.gov between January 1, 2003 and November 30, 2017 to assess trial design and the progress of combinations toward regulatory approval. Online surveys (N = 289, 23 questions total) were emailed to Principal Investigators (PIs) of early-phase National Cancer Institute and/or industry trials; 263 emails (91%) were received and 113 surveys completed (43%). Among phase 1 combination trials, 24.9% (95%CI: 15.3%, 34.4%) progressed to phase 2 or further; 18.7% (95%CI: 5.90%, 31.4%) progressed to phase 3 or regulatory approval; and 12.4% (95%CI: 0.00%, 25.5%) achieved regulatory approval. Observations of "clinical promise" in phase 1 combination studies were associated with higher rates of advancement past each milestone toward regulatory approval (cumulative OR = 11.9; p = 0.0002). Phase 1 combination study designs were concordant with Clinical Trial Design Task Force (CTD-TF) Recommendations 79.6% of the time (95%CI: 72.2%, 87.1%). Most discordances occurred where no plausible pharmacokinetic or pharmacodynamic interactions were expected. Investigator-defined "clinical promise" of a combination is associated with progress toward regulatory approval. Although concordance between study designs of phase 1 combination trials and CTD-TF Recommendations was relatively high, it may be beneficial to raise awareness about the best study design to use when no plausible pharmacokinetic or pharmacodynamic interactions are expected.

Leveraging National Cancer Institute Programmatic Collaboration for Uterine Cervix Cancer Patient Accrual in Puerto Rico.

Women in the U.S. Commonwealth of Puerto Rico (PR) have a higher age-adjusted incidence rate for uterine cervix cancer than the U.S. mainland as well as substantial access and economic barriers to cancer care. The National Cancer Institute (NCI) funds a Minority/Underserved NCI Community Oncology Research Program in PR (PRNCORP) as part of a national network of community-based health-care systems to conduct multisite cancer clinical trials in diverse populations. Participation by the PRNCORP in NCI's uterine cervix cancer clinical trials, however, has remained limited. This study reports on the findings of an NCI site visit in PR to assess barriers impeding site activation and accrual to its sponsored gynecologic cancer clinical trials. Qualitative, semi-structured individual, and group interviews were conducted at six PRNCORP-affiliated locations to ascertain: long-term trial accrual objectives; key stakeholders in PR that address uterine cervix cancer care; key challenges or barriers to activating and to enrolling patients in NCI uterine cervix cancer treatment trials; and resources, policies, or procedures in place or needed on the island to support NCI-sponsored clinical trials. An NCI-sponsored uterine cervix cancer radiation-chemotherapy intervention clinical trial (NCT02466971), already activated on the island, served as a test case to identify relevant patient accrual and site barriers. The site visit identified five key barriers to accrual: (1) lack of central personnel to coordinate referrals for treatment plans, medical tests, and medical imaging across the island's clinical trial access points; (2) patient insurance coverage; (3) lack of a coordinated brachytherapy schedule at San Juan-centric service providers; (4) limited credentialed radiotherapy machines island-wide; and (5) too few radiology medical physicists tasked to credential trial-specified positron emission tomography scanners island-wide. PR offers a unique opportunity to study overarching and tactical strategies for improving accrual to NCI-sponsored gynecologic cancer clinical trials. Interview findings support adding and re-tasking personnel for coordinated trial-eligible patient referral, accrual, and treatment.

Meeting the Challenge: The National Cancer Institute's Central Institutional Review Board for Multi-Site Research.

The National Institutes of Health (NIH) issued a new policy that requires a single institutional review board (IRB) of record be used for all protocols funded by the NIH that are carried out at more than one site in the United States, effective January 2018. This policy affects several hundred clinical trials opened annually across the NIH. Limited data exist to compare the use of a single IRB to that of multiple local IRBs, so some institutions are resistant to or distrustful of single IRBs. Since 2001, the National Cancer Institute (NCI) has funded a central IRB (CIRB) that provides human patient reviews for its extensive national cancer clinical trials program. This paper presents data to show the adoption, efficiencies gained, and satisfaction of the CIRB among NCI trial networks and reviews key lessons gleaned from 16 years of experience that may be informative for others charged with implementation of the new NIH single-IRB policy.

Raising Public Awareness of Clinical Trials: Development of Messages for a National Health Communication Campaign.

Clinical trials are essential for developing new and effective treatments and improving patient quality of life; however, many trials cannot answer their primary research questions because they fall short of their recruitment goals. This article reports the results of formative research conducted in two populations, the public and primary care physicians, to identify messages that may raise awareness and increase interest in clinical trials and be used in a national communication campaign. Results suggested that participants were primarily motivated to participate in clinical trials out of a self-interest to help themselves first. Messages illustrated that current treatments were tested via clinical trials, helped normalize trials as routine practices, and reduced concerns over trying something new first. Participants wanted messages that portray trials as state-of-the-art choices that offer some hope, show people like themselves, and are described in a clear, concise manner with actionable steps for them to take. The study revealed some differences in message salience, with healthy audiences exhibiting lower levels of interest. Our results suggest that targeted messages are needed, and that communication with primary health-care providers is an important and necessary component in raising patient awareness of the importance of clinical trials.

Challenges Facing Early Phase Trials Sponsored by the National Cancer Institute: An Analysis of Corrective Action Plans to Improve Accrual.

Accruing patients in a timely manner represents a significant challenge to early phase cancer clinical trials. The NCI Cancer Therapy Evaluation Program analyzed 19 months of corrective action plans (CAP) received for slow-accruing phase I and II trials to identify slow accrual reasons, evaluate whether proposed corrective actions matched these reasons, and assess the CAP impact on trial accrual, duration, and likelihood of meeting primary scientific objectives. Of the 135 CAPs analyzed, 69 were for phase I trials and 66 for phase II trials. Primary reasons cited for slow accrual were safety/toxicity (phase I: 48%), design/protocol concerns (phase I: 42%, phase II: 33%), and eligibility criteria (phase I: 41%, phase II: 35%). The most commonly proposed corrective actions were adding institutions (phase I: 43%, phase II: 85%) and amending the trial to change eligibility or design (phase I: 55%, phase II: 44%). Only 40% of CAPs provided proposed corrective actions that matched the reasons given for slow accrual. Seventy percent of trials were closed to accrual at time of analysis (phase I = 48; phase II = 46). Of these, 67% of phase I and 70% of phase II trials met their primary objectives, but they were active three times longer than projected. Among closed trials, 24% had an accrual rate increase associated with a greater likelihood of meeting their primary scientific objectives. Ultimately, trials receiving CAPs saw improved accrual rates. Future trials may benefit from implementing CAPs early in trial life cycles, but it may be more beneficial to invest in earlier accrual planning. Clin Cancer Res; 22(22); 5408-16. ©2016 AACRSee related commentary by Mileham and Kim, p. 5397.

Power of an effective clinical conversation: improving accrual onto clinical trials.

The National Cancer Institute (NCI) is actively transforming clinical trials to revitalize the clinical trials system and improve patient accrual. For more than 30 years, NCI has provided information and communication resources about cancer clinical trials. The Institute supports a clinical trials Web site (www.cancer.gov/clinicaltrials) that receives nearly a half million page views a month. In addition, NCI's Cancer Information Service (800-4-CANCER, chat and e-mail) responds to 1,750 clinical trial inquiries every month. Although these numbers suggest that a high volume of clinical trial information is being exchanged between NCI, the public, and providers, most patients decide whether to participate in clinical trials during the patient-provider interaction.

Assessing the need for a standardized cancer HUman Biobank (caHUB): findings from a national survey with cancer researchers.

BACKGROUND: Before developing a national standardized cancer HUman Biobank (caHUB), the National Cancer Institute sought feedback from the cancer research community. METHODS: NCI conducted an online survey (N = 727) about current biospecimen needs and reactions to creating a national resource cancer researchers and others. RESULTS: Most (56%) participants obtained biospecimens within their own institutions, and 63% wanted more information about their biospecimens. Large proportions reported difficulty obtaining biospecimens of adequate numbers (39%) and quality (47%). Low-quality biospecimens resulted in 60% questioning their findings and 81% limiting the scope of their work. Nine in every 10 (91.3%) respondents reacted positively to the idea of a national biospecimen resource, with 62% reporting that they would obtain biospecimens from it and 53% reporting that they would be willing to contribute biospecimens to it. CONCLUSIONS: Initial reactions to caHUB were positive and seen as a feasible option to addressing respondents' research challenges. National Cancer Institute will need to address several concerns to assure its adoption, including standardization and sustainability.

Stakeholder research on biospecimen needs and reactions to the development of a national cancer human biobank by the National Cancer Institute.

An initial survey conducted by the National Cancer Institute (NCI) in October 2008 with cancer researchers around the country revealed both a need and support for the development of a national cancer HUman Biobank (caHUB). NCI sought additional feedback from decision makers whose organizations are potential users of a caHUB and who would have a direct influence on whether or not their organizations would participate in a caHUB. NCI commissioned online discussion groups with executive-level decision makers at academic institutions with cancer research programs and pharmaceutical/biotechnology organizations. Across both groups, a clear need for a national caHUB was uniformly expressed. While having a broad range of biospecimens--especially those hard to obtain--in one location was important, stakeholders agreed that the level of standardization the caHUB could offer was the most important benefit. Stakeholders believed the development of standard operating procedures around collection, storage, and quality assessment of biospecimens would be the greatest contribution of the caHUB, allowing more collaboration and higher confidence in research results. Barriers to contribution and/or use of the caHUB focused on funding and resources required of participants, concerns over standard operating procedures, and impositions on their organizations' intellectual property. Findings from the qualitative research are consistent with previous research and point to an overwhelming need for a solution that will address growing concerns about access and availability of quality biospecimens to conduct cancer research and ultimately expedite future discoveries to treat and cure cancer.

Usability and accessibility in consumer health informatics current trends and future challenges.

It is a truism that, for innovative eHealth systems to have true value and impact, they must first and foremost be usable and accessible by clinicians, consumers, and other stakeholders. In this paper, current trends and future challenges in the usability and accessibility of consumer health informatics will be described. Consumer expectations of their healthcare providers and healthcare records in this new era of consumer-directed care will be explored, and innovative visualizations, assistive technologies, and other ways that healthcare information is currently being provided and/or shared will be described. Challenges for ensuring the usability of current and future systems will also be discussed. An innovative model for conducting systematic, timely, user-centered research on consumer-facing websites at the National Cancer Institute (NCI) and the ongoing efforts at the National Institute of Standards and Technology (NIST) to promote health information technology (HIT) usability standards and evaluation criteria will also be presented.

AccrualNet: Addressing Low Accrual Via a Knowledge-Based, Community of Practice Platform.

PURPOSE: Present the design and initial evaluation of a unique, Web-enabled platform for the development of a community of practice around issues of oncology clinical trial accrual. METHODS: The National Cancer Institute (NCI) conducted research with oncology professionals to identify unmet clinical trial accrual needs in the field. In response, a comprehensive platform for accrual resources, AccrualNet, was created by using an agile development process, storyboarding, and user testing. Literature and resource searches identified relevant content to populate the site. Descriptive statistics were tracked for resource and site usage. Use cases were defined to support implementation. RESULTS: ACCRUALNET HAS FIVE LEVELS: (1) clinical trial macrostages (prestudy, active study, and poststudy); (2) substages (developing a protocol, selecting a trial, preparing to open, enrolling patients, managing the trial, retaining participants, and lessons learned); (3) strategies for each substage; (4) multiple activities for each strategy; and (5) multiple resources for each activity. Since its launch, AccrualNet has had more than 45,000 page views, with the Tools & Resources, Conversations, and Training sections being the most viewed. Total resources have increased 69%, to 496 items. Analysis of articles in the site reveals that 22% are from two journals and 46% of the journals supplied a single article. To date, there are 29 conversations with 43 posts. Four use cases are discussed. CONCLUSION: AccrualNet represents a unique, centralized comprehensive-solution platform to systematically capture accrual knowledge for all stages of a clinical trial. It is designed to foster a community of practice by encouraging users to share additional strategies, resources, and ideas.

Assessing the impact of user-centered research on a clinical trial eHealth tool via counterbalanced research design.

OBJECTIVE: Informatics applications have the potential to improve participation in clinical trials, but their design must be based on user-centered research. This research used a fully counterbalanced experimental design to investigate the effect of changes made to the original version of a website, http://BreastCancerTrials.org/, and confirm that the revised version addressed and reinforced patients' needs and expectations. DESIGN: Participants included women who had received a breast cancer diagnosis within the last 5 years (N=77). They were randomized into two groups: one group used and reviewed the original version first followed by the redesigned version, and the other group used and reviewed them in reverse order. MEASUREMENTS: The study used both quantitative and qualitative measures. During use, participants' click paths and general reactions were observed. After use, participants were asked to answer survey items and open-ended questions to indicate their reactions and which version they preferred and met their needs and expectations better. RESULTS: Overall, the revised version of the site was preferred and perceived to be clearer, easier to navigate, more trustworthy and credible, and more private and safe overall. However, users who viewed the original version last had similar attitudes toward both versions. CONCLUSION: By applying research findings to the redesign of a website for clinical trial searching, it was possible to re-engineer the interface to better support patients' decisions to participate in clinical trials. The mechanisms of action in this case appeared to revolve around creating an environment that supported a sense of personal control and decisional autonomy.

Validating a health consumer segmentation model: behavioral and attitudinal differences in disease prevention-related practices.

While researchers typically have segmented audiences by demographic or behavioral characteristics, psychobehavioral segmentation schemes may be more useful for developing targeted health information and programs. Previous research described a four segment psychobehavioral segmentation scheme-and a 10-item screening instrument used to identify the segments-based predominantly on people's orientation to their health (active vs. passive) and their degree of independence in health care decision making (independent vs. dependent). This study builds on this prior research by assessing the screening instrument's validity with an independent dataset and exploring whether people with distinct psychobehavioral orientations have different disease prevention attitudes and preferences for receiving information in the primary care setting. Data come from 1,650 respondents to a national mail panel survey. Using the screening instrument, respondents were segmented into four groups-independent actives, doctor-dependent actives, independent passives, and doctor-dependent passives. Consistent with the earlier research, there were clear differences in health-related attitudes and behaviors among the four segments. Members of three segments appear quite receptive to receiving disease prevention information and assistance from professionals in the primary care setting. Our findings provide further indication that the screening instrument and corresponding segmentation strategy may offer a simple, effective tool for targeting and tailoring information and other health programming to the unique characteristics of distinct audience segments.

Opportunities and barriers to disease prevention counseling in the primary care setting: a multisite qualitative study with US health consumers.

The purpose of this study is to understand people's receptivity to seeking out disease prevention counseling from their primary care provider. Since patients' openness to health messages may vary depending on how they seek out their health information, participants were segmented into one of four unique information-seeking groups. This study explores the differences among these groups, what approaches would be most effective in motivating different health consumers to seek out behavioral counseling in the primary care setting and the opportunities during the medical visit most appropriate for this counseling. To this end, a total of 32 focus groups were conducted with American adults. Participants were segmented by information-seeking orientation (independent actives, doctor-dependent actives, independent passives and doctor-dependent passives), age and gender. Findings showed that participants of the four information-seeking groups possessed distinct differences in their desire for and perceived barriers to requesting counseling from their provider. Overall, participants wanted prevention counseling to include tailored information, encouragement and follow-up. Participants among the various segments identified two key windows of opportunity-during a routine checkup and when discussing their family history-where patients and providers can incorporate more in-depth prevention discussions into the medical visit. Findings from this study suggest that targeting health messages according to health consumers' information-seeking orientations may provide an effective tool for practitioners. Additionally, many health consumers are open to behavioral counseling in the primary care setting and would be satisfied if this counseling were integrated into traditional procedures, such as during a routine checkup or when discussing their family medical history.

Outside the box: will information technology be a viable intervention to improve the quality of cancer care?

The use of health information technology (IT) to resolve the crisis in communication inherent within the fragmented service environment of medical care in the United States is a strategic priority for the Department of Health and Human Services. Yet the deployment of health IT alone is not sufficient to improve quality in health service delivery; what is needed is a human factors approach designed to optimize the balance between health-care users, health-care providers, policies, procedures, and technologies. An evaluation of interface issues between primary and specialist care related to cancer reveals opportunities for human factors improvement along the cancer care continuum. Applications that emphasize cognitive support for prevention recommendations and that encourage patient engagement can help create a coordinated health-care environment conducive to cancer prevention and early detection. An emphasis on reliability, transparency, and accountability can help improve the coordination of activities among multiple service providers during diagnosis and treatment. A switch in emphasis from a transaction-based approach to one emphasizing long-term support for healing relationships should help improve patient outcomes during cancer survivorship and end-of-life care. Across the entire continuum of care, an emphasis on "meaningful use" of health IT-rather than on IT as an endpoint-should help put cancer on a path toward substantive continuous quality improvement. The accompanying research questions will focus on reducing the variance between the social and technical subsystems as IT is used to improve patient outcomes across the interfaces of care.

Using the Internet to search for cancer clinical trials: a comparative audit of clinical trial search tools.

Advancing the clinical trial research process to improve cancer treatment necessitates helping people with cancer identify and enroll in studies, and researchers are using the power of the Internet to facilitate this process. This study used a content analysis of online cancer clinical trial search tools to understand what people with cancer might encounter. The content analysis revealed that clinical trial search tools were easy to identify using a popular search engine, but their functionality and content varied greatly. Most required that users be fairly knowledgeable about their medical condition and sophisticated in their web navigation skills. The ability to search by a specific health condition or type of cancer was the most common search strategy. The more complex tools required that users input detailed information about their personal medical history and have knowledge of specific clinical trial terminology. Search tools, however, only occasionally advised users to consult their doctors regarding clinical trial decision-making. This, along with the complexity of the tools suggests that online search tools may not adequately facilitate the clinical trial recruitment process. Findings from this analysis can be used as a framework from which to systematically examine actual consumer experience with online clinical trial search tools.