Audit and feedback (A&F) is a common strategy for helping health providers to implement evidence into practice. Despite being extensively studied, health care A&F interventions remain variably ...effective, with overall effect sizes that have not improved since 2003. Contributing to this stagnation is the fact that most health care A&F interventions have largely been designed without being informed by theoretical understanding from the behavioral and social sciences. To determine if the trend can be improved, the objective of this study was to develop a list of testable, theory-informed hypotheses about how to design more effective A&F interventions.
Using purposive sampling, semi-structured 60-90-min telephone interviews were conducted with experts in theories related to A&F from a range of fields (e.g., cognitive, health and organizational psychology, medical decision-making, economics). Guided by detailed descriptions of A&F interventions from the health care literature, interviewees described how they would approach the problem of designing improved A&F interventions. Specific, theory-informed hypotheses about the conditions for effective design and delivery of A&F interventions were elicited from the interviews. The resulting hypotheses were assigned by three coders working independently into themes, and categories of themes, in an iterative process.
We conducted 28 interviews and identified 313 theory-informed hypotheses, which were placed into 30 themes. The 30 themes included hypotheses related to the following five categories: A&F recipient (seven themes), content of the A&F (ten themes), process of delivery of the A&F (six themes), behavior that was the focus of the A&F (three themes), and other (four themes).
We have identified a set of testable, theory-informed hypotheses from a broad range of behavioral and social science that suggest conditions for more effective A&F interventions. This work demonstrates the breadth of perspectives about A&F from non-healthcare-specific disciplines in a way that yields testable hypotheses for healthcare A&F interventions. These results will serve as the foundation for further work seeking to set research priorities among the A&F research community.
AMPK attenuates CD40‐mediated inflammatory activity in myeloid APC; its activity in both APC and T cells contributes to T cell functional polarization.
AMPK is a serine/threonine kinase that ...regulates energy homeostasis and metabolic stress in eukaryotes. Previous work from our laboratory, as well as by others, has provided evidence that AMPKα1 acts as a negative regulator of TLR‐induced inflammatory function. Herein, we demonstrate that AMPKα1‐deficient macrophages and DCs exhibit heightened inflammatory function and an enhanced capacity for antigen presentation favoring the promotion of Th1 and Th17 responses. Macrophages and DCs generated from AMPKα1‐deficient mice produced higher levels of proinflammatory cytokines and decreased production of the anti‐inflammatory cytokine IL‐10 in response to TLR and CD40 stimulation as compared with WT cells. In assays of antigen presentation, AMPKα1 deficiency in the myeloid APC and T cell populations contributed to enhanced IL‐17 and IFN‐γ production. Focusing on the CD154–CD40 interaction, we found that CD40 stimulation resulted in increased phosphorylation of ERK1/2, p38, and NF‐κB p65 and decreased activation of the anti‐inflammatory Akt ‐GSK3β‐CREB pathway in DCs deficient for AMPKα1. Our data demonstrate that AMPKα1 serves to attenuate LPS and CD40‐mediated proinflammatory activity of myeloid APCs and that AMPKα1 activity in both APC and T cells contributes to T cell functional polarization during antigen presentation.
Abstract Purpose A dearth in pediatric drug development often leaves pediatricians with no alternative but to prescribe unlicensed or off-label drugs with a resultant increased risk of adverse ...events. We present the current status of pediatric drug development and, based on our data analysis, clarify the problems in this area. Further action is proposed to improve the drug development that has pediatric therapeutic orphan status. Methods We analyzed all Phase II/III and Phase III trials in ClinicalTrials.gov that only included pediatric participants (<18 years old) between 2006 and 2014. Performance index, an indicator of pediatric drug development, was calculated by dividing the annual number of pediatric clinical trials by million pediatric populations acquired from Census.gov. Effects of the 2 Japanese premiums introduced in 2010, for the enhancement of pediatric drug development, were analyzed by comparing mean performance index prepremiums (2006-2009) and postpremiums (2010-2014) among Japan, the European Union, and the United States. The European Union Clinical Trials Register and published reports from the European Medicines Agency were also surveyed to investigate the Paediatric Committee effect on pediatric clinical trials in the European Union. Findings Mean difference of the performance index in prepremiums and postpremiums between Japan and the European Union were 0.296 ( P < 0.001) and 0.066 ( P = 0.498), respectively. Those between Japan and the United States were 0.560 ( P < 0.001) and 0.281 ( P = 0.002), indicating that pediatric drug development in Japan was more active after the introduction of these premiums, even reaching the level of the European Union. The Pediatric Regulation and the Paediatric Committee promoted pediatric drug development in the European Union. The registered number of clinical trials that includes at least 1 participants <18 years old in the European Union Clinical Trials Register increased by 247 trials (from 672) in the 1000 days after regulation. The ratio of pediatric clinical trials with an approved Paediatric Investigation Plan increased to >15% after 2008. Implications Recruitment and ethical obstacles make conducting pediatric clinical trials challenging. An improved operational framework for conducting clinical trials should mirror the ever-improving regulatory framework that incentivizes investment in pediatric clinical trials. Technological approaches, enhancements in electronic medical record systems, and community approaches that actively incorporate input from physicians, researchers, and patients could offer a sustainable solution to recruitment of pediatric study participants. The key therefore is to improve pediatric pharmacotherapy collaboration among industry, government, academia, and community. Expanding the regulatory steps taken in the European Union, United States, and Japan and using innovative clinical trial tools can move pediatric pharmacotherapy out of its current therapeutic orphan state.
Recruiting participants to clinical trials is an ongoing challenge, and relatively little is known about what recruitment strategies lead to better recruitment. Recruitment interventions can be ...considered complex interventions, often involving multiple components, targeting a variety of groups, and tailoring to different groups. We used the Template for Intervention Description and Replication (TIDieR) reporting checklist (which comprises 12 items recommended for reporting complex interventions) to guide the assessment of how recruitment interventions are described. We aimed to (1) examine to what extent we could identify information about each TIDieR item within recruitment intervention studies, and (2) observe additional detail for each item to describe useful variation among these studies.
We identified randomized, nested recruitment intervention studies providing recruitment or willingness to participate rates from two sources: a Cochrane review of trials evaluating strategies to improve recruitment to randomized trials, and the Online Resource for Research in Clinical triAls database. First, we assessed to what extent authors reported information about each TIDieR item. Second, we developed descriptive categorical variables for 7 TIDieR items and extracting relevant quotes for the other 5 items.
We assessed 122 recruitment intervention studies. We were able to extract information relevant to most TIDieR items (e.g., brief rationale, materials, procedure) with the exception of a few items that were only rarely reported (e.g., tailoring, modifications, planned/actual fidelity). The descriptive variables provided a useful overview of study characteristics, with most studies using various forms of informational interventions (55%) delivered at a single time point (90%), often by a member of the research team (59%) in a clinical care setting (41%).
Our TIDieR-based variables provide a useful description of the core elements of complex trial recruitment interventions. Recruitment intervention studies report core elements of complex interventions variably; some process elements (e.g., mode of delivery, location) are almost always described, while others (e.g., duration, fidelity) are reported infrequently, with little indication of a reason for their absence. Future research should explore whether these TIDieR-based variables can form the basis of an approach to better reporting of elements of successful recruitment interventions.
Audit and feedback (A&F) interventions are one of the most common approaches for implementing evidence-based practices. A key barrier to more effective A&F interventions is the lack of a ...theory-guided approach to the accumulation of evidence. Recent interviews with theory experts identified 313 theory-informed hypotheses, spread across 30 themes, about how to create more effective A&F interventions. In the current survey, we sought to elicit from stakeholders which hypotheses were most likely to advance the field if studied further.
From the list of 313, three members of the research team identified 216 that were clear and distinguishable enough for prioritization. A web-based survey was then sent to 211 A&F intervention stakeholders asking them to choose up to 50 'priority' hypotheses following the header "A&F interventions will be more effective if…". Analyses included frequencies of endorsement of the individual hypotheses and themes into which they were grouped.
68 of the 211 invited participants responded to the survey. Seven hypotheses were chosen by > 50% of respondents, including A&F interventions will be more effective… "if feedback is provided by a trusted source"; "if recipients are involved in the design/development of the feedback intervention"; "if recommendations related to the feedback are based on good quality evidence"; "if the behaviour is under the control of the recipient"; "if it addresses barriers and facilitators (drivers) to behaviour change"; "if it suggests clear action plans"; and "if target/goal/optimal rates are clear and explicit". The most endorsed theme was Recipient Priorities (four hypotheses were chosen 92 times as a 'priority' hypotheses).
This work determined a set of hypotheses thought by respondents to be to be most likely to advance the field through future A&F intervention research. This work can inform a coordinated research agenda that may more efficiently lead to more effective A&F interventions.
Clinical trial recruitment is a continuing challenge for medical researchers. Previous efforts to improve study recruitment have rarely been informed by theories of human decision making and behavior ...change. We investigate the trial recruitment strategies reported by study recruiters, guided by two influential theoretical frameworks: shared decision-making (SDM) and the Theoretical Domains Framework (TDF) in order to explore the utility of these frameworks in trial recruitment.
We interviewed all nine active study recruiters from a multi-site, open-label pilot trial assessing the feasibility of a large-scale randomized trial. Recruiters were primarily nurses or master's-level research assistants with a range of 3 to 30 years of experience. The semi-structured interviews included questions about the typical recruitment encounter, questions concerning the main components of SDM (e.g. verifying understanding, directive vs. non-directive style), and questions investigating the barriers to and drivers of their recruitment activities, based on the TDF. We used directed content analysis to code quotations into TDF domains, followed by inductive thematic analysis to code quotations into sub-themes within domains and overarching themes across TDF domains. Responses to questions related to SDM were aggregated according to level of endorsement and informed the thematic analysis.
The analysis helped to identify 28 sub-themes across 11 domains. The sub-themes were organized into six overarching themes: coordinating between people, providing guidance to recruiters about challenges, providing resources to recruiters, optimizing study flow, guiding the recruitment decision, and emphasizing the benefits to participation. The SDM analysis revealed recruiters were able to view recruitment interactions as successful even when enrollment did not proceed, and most recruiters took a non-directive (i.e. providing patients with balanced information on available options) or mixed approach over a directive approach (i.e. focus on enrolling patient in study). Most of the core SDM constructs were frequently endorsed.
Identified sub-themes can be linked to TDF domains for which effective behavior change interventions are known, yielding interventions that can be evaluated as to whether they improve recruitment. Despite having no formal training in shared decision-making, study recruiters reported practices consistent with many elements of SDM. The development of SDM training materials specific to trial recruitment could improve the informed decision-making process for patients.
To describe the extent to which pragmatic trials underachieved or overachieved their target sample sizes, examine explanations and identify characteristics associated with under-recruitment and ...over-recruitment.
Secondary analysis of an existing database of primary trial reports published during 2014-2019, registered in ClinicalTrials.gov, self-labelled as pragmatic and with target and achieved sample sizes available.
Of 372 eligible trials, the prevalence of under-recruitment (achieving <90% of target sample size) was 71 (19.1%) and of over-recruitment (>110% of target) was 87 (23.4%). Under-recruiting trials commonly acknowledged that they did not achieve their targets (51, 71.8%), with the majority providing an explanation, but only 11 (12.6%) over-recruiting trials acknowledged recruitment excess. The prevalence of under-recruitment in individually randomised versus cluster randomised trials was 41 (17.0%) and 30 (22.9%), respectively; prevalence of over-recruitment was 39 (16.2%) vs 48 (36.7%), respectively. Overall, 101 025 participants were recruited to trials that did not achieve at least 90% of their target sample size. When considering trials with over-recruitment, the total number of participants recruited in excess of the target was a median (Q1-Q3) 319 (75-1478) per trial for an overall total of 555 309 more participants than targeted. In multinomial logistic regression, cluster randomisation and lower journal impact factor were significantly associated with both under-recruitment and over-recruitment, while using exclusively routinely collected data and educational/behavioural interventions were significantly associated with over-recruitment; we were unable to detect significant associations with obtaining consent, publication year, country of recruitment or public engagement.
A clear explanation for under-recruitment or over-recruitment in pragmatic trials should be provided to encourage transparency in research, and to inform recruitment to future trials with comparable designs. The issues and ethical implications of over-recruitment should be more widely recognised by trialists, particularly when designing cluster randomised trials.
There is a concern that the apparent effectiveness of interventions tested in clinical trials may not be an accurate reflection of their actual effectiveness in usual practice. Pragmatic randomized ...controlled trials (RCTs) are designed with the intent of addressing this discrepancy. While pragmatic RCTs may increase the relevance of research findings to practice they may also raise new ethical concerns (even while reducing others). To explore this question, we interviewed key stakeholders with the aim of identifying potential ethical challenges in the design and conduct of pragmatic RCTs with a view to developing future guidance on these issues.
Interviews were conducted with clinical investigators, methodologists, patient partners, ethicists, and other knowledge users (e.g., regulators). Interviews covered experiences with pragmatic RCTs, ethical issues relevant to pragmatic RCTs, and perspectives on the appropriate oversight of pragmatic RCTs. Interviews were coded inductively by two coders. Interim and final analyses were presented to the broader team for comment and discussion before the analytic framework was finalized.
We conducted 45 interviews between April and September 2018. Interviewees represented a range of disciplines and jurisdictions as well as varying content expertise. Issues of importance in pragmatic RCTs were (1) identification of relevant risks from trial participation and determination of what constitutes minimal risk; (2) determining when alterations to traditional informed consent approaches are appropriate; (3) the distinction between research, quality improvement, and practice; (4) the potential for broader populations to be affected by the trial and what protections they might be owed; (5) the broader range of trial stakeholders in pragmatic RCTs, and determining their roles and responsibilities; and (6) determining what constitutes "usual care" and implications for trial reporting.
Our findings suggest both the need to discuss familiar ethical topics in new ways and that there are new ethical issues in pragmatic RCTs that need greater attention. Addressing the highlighted issues and developing guidance will require multidisciplinary input, including patient and community members, within a broader and more comprehensive analysis that extends beyond consent and attends to the identified considerations relating to risk and stakeholder roles and responsibilities.
Ensuring adequate, informed, and timely participation in clinical trials is a multifactorial problem. We have previously developed a systematic, tailorable survey development approach that is ...informed by theory, can identify barriers and enablers to participation, and can suggest recruitment strategies to address these issues. In this study, we surveyed subscribers to the Canadian Breast Cancer Network (CBCN) in order to identify a comprehensive list of theory-informed barriers and enablers relevant to participation in a hypothetical breast cancer trial.
We developed and conducted an online survey of breast cancer patients informed by the Theoretical Domains Framework and designed to determine previous experience with clinical trials, knowledge about clinical trials, and importance of a comprehensive list of barriers and enablers to trial participation. Participants were contacted by email or through social media.
From 2451 subscribers of the CBCN, we received 244 responses and 210 completed surveys (244/2451 or 9.9% participation, 210/244 or 86.1% completion). A total of 38% of respondents indicated experience in trial participation, but 83% indicated confidence in their knowledge about clinical trials. Those who had previously participated in clinical trials were more confident in their knowledge (χ
= 6.77,
= 0.009) and answered more knowledge questions (t = -3.90
= 0.000). Endorsed barriers and enablers to participation included 39 factors across 12 of 14 domains relevant to behaviour change. Our approach identifies barriers that might be meaningfully addressed by careful knowledge provision ('
'), those that may require other theory-informed approaches to address ('
'; '
'), and those that may require tailored approaches depending on participant differences such as previous experience in trials ('
').
This work demonstrates that a comprehensive, theory-guided survey of barriers and enablers to participation in breast cancer clinical trials is feasible, can lead to detailed knowledge about the issues related to participation in specific trials, and most importantly, can lead to insights about evidence-based ways to better support patient participation.
Introduction
To improve dementia care delivery for persons across all backgrounds, it is imperative that health equity is integrated into pragmatic trials.
Methods
We reviewed 62 pragmatic trials of ...people with dementia published 2014 to 2019. We assessed health equity in the objectives; design, conduct, analysis; and reporting using PROGRESS‐Plus which stands for Place of residence, Race/ethnicity, Occupation, Gender/sex, Religion, Education, Socioeconomic status, Social capital, and other factors such as age and disability.
Results
Two (3.2%) trials incorporated equity considerations into their objectives; nine (14.5%) engaged with communities; 4 (6.5%) described steps to increase enrollment from equity‐relevant groups. Almost all trials (59, 95.2%) assessed baseline balance for at least one PROGRESS‐Plus characteristic, but only 10 (16.1%) presented subgroup analyses across such characteristics. Differential recruitment, attrition, implementation, adherence, and applicability across PROGRESS‐Plus were seldom discussed.
Discussion
Ongoing and future pragmatic trials should more rigorously integrate equity considerations in their design, conduct, and reporting.
Highlights
Few pragmatic trials are explicitly designed to inform equity‐relevant objectives.
Few pragmatic trials take steps to increase enrollment from equity‐relevant groups.
Disaggregated results across equity‐relevant groups are seldom reported.
Adherence to existing tools (e.g., IMPACT Best Practices, CONSORT‐Equity) is key.
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