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We established a large database of trials to serve as a resource for future methodological and ethical analyses. Here, we use meta-data to describe the broad landscape of pragmatic trials including research areas, identification as pragmatic, quality of trial registry data and enrolment. Trials were identified by a validated search filter and included if a primary report of a health-related randomized trial published January 2014-April 2019. Data were collated from MEDLINE, Web of Science, ClinicalTrials.gov, and full text. 4337 eligible trials were identified from 13,065 records, of which 1988 were registered in ClinicalTrials.gov. Research areas were diverse, with the most common being general and internal medicine; public, environmental and occupational health; and health care sciences and services. The term “pragmatic” was seldom used in titles or abstracts. Several domains in ClinicalTrials.gov had questionable data quality. We estimated that one-fifth of trials under-accrued by at least 15%. There is a need to improve reporting of pragmatic trials and quality of trial registry data. Under accrual remains a challenge in pragmatic RCTs despite calls for more streamlined recruitment approaches. The diversity of pragmatic trials should be reflected in future ethical analyses.

Purpose of Review Randomized controlled trials (RCTs) in heart failure (HF) are becoming increasingly complex and expensive to conduct and if positive deliver expensive therapy tested only in selected populations. Recent Findings Electronic health records and clinical cardiovascular quality registries are providing opportunities for pragmatic and registry-based prospective randomized clinical trials (RRCTs). Simplified regulatory, ethics, and consent procedures; recruitment integrated into real-world care; and simplified or automated baseline and outcome collection allow assessment of study power and feasibility, fast and efficient recruitment, delivery of generalizable findings at low cost, and potentially evidence-based and novel use of generic drugs with low costs to society. Summary There have been no RRCTs in HF to date. Major challenges include generating funding, international collaboration, and the monitoring of safety and adherence for chronic HF treatments. Here, we use the Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure with Preserved Ejection Fraction (SPIRRIT-HFpEF), to be conducted in the Swedish Heart Failure Registry, to exemplify the advantages and challenges of HF RRCTs.

The “cohort multiple randomized controlled trial,” a new design for pragmatic trials, embeds multiple trials within a cohort. The cohort multiple RCT is an attractive alternative to conventional RCTs in fields where recruitment is slow, multiple new (competing) interventions for the same condition have to be tested, new interventions are highly preferred by patients and doctors, and the risk of disappointment bias, cross-over, and contamination is considerable. To prevent these unwanted effects, the cohort multiple RCT provides information on randomization to the intervention group/arm only, and only after randomization (i.e., prerandomization). To some, especially in a clinical setting, this is not ethically acceptable. In this article, we argue that prerandomization in the cohort multiple randomized controlled trial (cmRCT) can be avoided by adopting a staged-informed consent procedure. In the first stage, at entry into the cohort, all potential participants are asked for their informed consent to participate in a cohort study and broad consent to be either randomly selected to be approached for experimental interventions or to serve as control without further notice during participation in the cohort. In a second stage, at the initiation of an RCT within the cohort, informed consent to receive the intervention is then only sought in those randomly selected for the intervention arm. At the third stage, after completion of each RCT, all cohort participants receive aggregate disclosure of trial results. This staged-informed consent procedure avoids prerandomization in cmRCT and aims to keep participants actively engaged in the research process.

Background The clinical research enterprise is not producing the evidence decision makers arguably need in a timely and cost effective manner; research currently involves the use of labor-intensive parallel systems that are separate from clinical care. The emergence of pragmatic clinical trials (PCTs) poses a possible solution: these large-scale trials are embedded within routine clinical care and often involve cluster randomization of hospitals, clinics, primary care providers, etc. Interventions can be implemented by health system personnel through usual communication channels and quality improvement infrastructure, and data collected as part of routine clinical care. However, experience with these trials is nascent and best practices regarding design operational, analytic, and reporting methodologies are undeveloped. Methods To strengthen the national capacity to implement cost-effective, large-scale PCTs, the Common Fund of the National Institutes of Health created the Health Care Systems Research Collaboratory (Collaboratory) to support the design, execution, and dissemination of a series of demonstration projects using a pragmatic research design. Results In this article, we will describe the Collaboratory, highlight some of the challenges encountered and solutions developed thus far, and discuss remaining barriers and opportunities for large-scale evidence generation using PCTs. Conclusion A planning phase is critical, and even with careful planning, new challenges arise during execution; comparisons between arms can be complicated by unanticipated changes. Early and ongoing engagement with both health care system leaders and front-line clinicians is critical for success. There is also marked uncertainty when applying existing ethical and regulatory frameworks to PCTS, and using existing electronic health records for data capture adds complexity.

Background The need for high-quality evidence that is applicable in real-world, routine settings continues to increase. Pragmatic trials are designed to evaluate the effectiveness of interventions in real-world settings, whereas explanatory trials aim to test whether an intervention works under optimal situations. There is a continuum between explanatory and pragmatic trials. Most trials have aspects of both, making it challenging to label and categorize a trial and to evaluate its potential for translation into practice. Methods We summarize our experience applying the Pragmatic-Explanatory Continuum Indicator Summary (PRECIS) combined with external validity items based on the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework to three studies to provide a more robust and comprehensive assessment of trial characteristics related to translation of research. We summarize lessons learned using domains from the combined frameworks for use in study planning, evaluating specific studies, and reviewing the literature and make recommendations for future use. Results A variety of coders can be trained to use the PRECIS and RE-AIM domains. These domains can also be used for diverse purposes, content areas, and study types, but are not without challenges. Both PRECIS and RE-AIM domains required modification in two of the three studies to evaluate and rate domains specific to study type. Lessons learned involved: dedicating enough time for training activities related to the domains; use of reviewers with a range of familiarity with specific study protocols; how to best adapt ratings that reflect complex study designs; and differences of opinion regarding the value of creating a composite score for these criteria. Conclusions Combining both frameworks can specifically help identify where and how a study is and is not pragmatic. Using both PRECIS and RE-AIM allows for standard reporting of key study characteristics related to pragmatism and translation. Such measures should be used more consistently to help plan more pragmatic studies, evaluate progress, increase transparency of reporting, and integrate literature to facilitate translation of research into practice and policy.

Background Lack of data integrity is a common problem in randomized clinical trials and is more serious in economic evaluations conducted alongside explanatory clinical trials. Despite pragmatic randomized controlled trials (pRCTs) becoming recognized as the best design for economic evaluations, information on the proportion, handling approaches, and reporting quality of missing data in pRCTs-based economic evaluations remains limited. This study aimed to investigate the quantity and reporting quality of missing data in economic evaluations conducted alongside pragmatic clinical trials. Methods In this cross-sectional survey, data were extracted from PubMed and OVID (Embase, CENTRAL, HTA database, and NHS EED) from January 1, 2010, to April 24, 2022. Economic evaluations conducted alongside pRCTs were included. Two independent reviewer groups identified relevant articles, and data were extracted by three groups comprising two reviewers each. Descriptive analyses were performed to assess the characteristics of the included studies, missingness in the included studies, and handling of missing data. Results Overall, 715 studies were identified, of which 152 met the inclusion criteria. In total, 113, 119, and 132 articles reported missing data, costs, and effects, respectively. More than 50% (58/113) of the articles reported the proportion or quantity of overall missingness, and 64.71% and 54.55% reported missing costs and effects, respectively. The proportion of missingness of < 5% in the overall group was 3.45%, whereas the proportions of missing costs and effects were both < 10% (5.26% vs. 8.45%, respectively). In terms of the proportion of missing data, the overall missingness rate was 30.22% in 58 studies, whereas the median proportion of missing data was slightly higher than that of missing effects (30.92% vs. 27.78%). Of the included studies, 56 (36.84%) conducted a sensitivity analysis on handling missing data. Of these, 12.50% reported missing mechanisms, and 83.93% examined handling methods. Conclusions Insufficient description and reporting of missing data, along with a high proportion of missing data in pRCT-based economic evaluations, could decrease the reliability and extrapolation of conclusions, leading to misleading decision-making.

Background New considerations during the ethical review processes may emerge from innovative, yet unfamiliar operational methods enabled in pragmatic randomized controlled trials (RCT), potentially making institutional review board (IRB) evaluation more complex. In this manuscript, key components of the pragmatic “Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-term Effectiveness (ADAPTABLE)” randomized trial that required a reappraisal of the IRB submission, review, and approval processes are discussed. Main text ADAPTABLE is a pragmatic, multicenter, open-label RCT evaluating the comparative effectiveness of two doses of aspirin widely used for secondary prevention (81 mg and 325 mg) in 15,000 patients with an established history of atherosclerotic cardiovascular disease. The electronic informed consent form is completed online by the participants at the time of enrollment, and endpoint ascertainment is conducted through queries of electronic health records. IRB challenges encountered regarding centralized IRB evaluation, electronic informed consent, patient engagement, and risk determination in ADAPTABLE are described in this manuscript. The experience of ADAPTABLE encapsulates how pragmatic protocol components intended to facilitate the study conduct have been tempered by unexpected, yet justified concerns raised by local IRBs. How the lessons learned can be applied to future similar pragmatic trials is delineated. Conclusion Development of engaging communication channels between IRB and study personnel in pragmatic randomized trials as early as at the time of protocol design allows to reduce issues with IRB approval. Integrations of the lessons learned in ADAPTABLE regarding the IRB process for centralized IRBs, informed consent, patient engagement, and risk determination can be emulated and will be instrumental in future pragmatic studies.

The Health Insurance Portability and Accountability Act (HIPAA) aims to safeguard patient information; however, complex legal language may lead to confusion and mistrust, and hinder enrollment in clinical trials. To evaluate the effect of a standard HIPAA authorization included in mailed survey packets on study enrollment for a multi-site pragmatic trial. This study is nested within an advance care planning pragmatic trial at 50 primary care clinics across three University of California (UC) Health Systems. We included English and Spanish-speaking seriously ill patients. One third of eligible patients received and 2/3 did not receive the HIPAA authorization in their enrollment packet. We compared enrollment rates at 3 months and assessed the readability, understandability, and actionability of the standard HIPAA form using the Federal Plain Language Guidelines Checklist for Plain Language, the Automatic Readability Checker consensus calculator (grade 8 is the average reading level for US adults), and the Patient Education Materials Assessment Tool for Printable Materials (PEMAT-P, 0-100%, 70% considered the minimum). Of 4632 eligible patients (mean age 71, 48% women, 11% Spanish-speaking, 40% racial/ethnic minority); 1543 received a mailed enrollment packet with a HIPAA form and 3089 did not. Patients mailed the HIPAA form were less likely to enroll (10.2% vs. 14.8%, p < 0.001). The standard HIPAA form scored at the 12th grade reading level, had a PEMAT-P Understandability score of 42%, had an Actionability score of 40%, and only met 50% of Federal Plain Language Guideline Checklist items. The inclusion of a standard HIPAA authorization in mailed enrollment packets for a large pragmatic trial led to lower rates of study enrollment. This study informs how HIPAA authorization forms should be redesigned to be more accessible to patients to prevent unnecessary barriers to research enrollment.

BackgroundCurrent guidelines advise providers to assess smokers’ readiness to quit, then offer cessation therapies to smokers planning to quit and motivational interventions to smokers not planning to quit.ObjectivesWe examined the relationship between baseline stage of change (SOC), treatment utilization, and smoking cessation to determine whether the effect of a proactive smoking cessation intervention was dependent on smokers’ level of motivation to quit.DesignSecondary analysis of a multicenter randomized controlled trial.ParticipantsA total of 3006 current smokers, aged 18–80 years, at four Veterans Affairs (VA) medical centers.Interventions: Proactive care included proactive outreach (mailed invitation followed by telephone outreach), offer of smoking cessation services (telephone or face-to-face), and access to pharmacotherapy. Usual care participants had access to VA smoking cessation services and state telephone quitlines.Main MeasuresBaseline SOC measured with Readiness to Quit Ladder, and 6-month prolonged abstinence self-reported at 1 year.Key ResultsAt baseline, 35.8 % of smokers were in preparation, 38.2 % in contemplation, and 26.0 % in precontemplation. The overall interaction between SOC and treatment arm was not statistically significant (p = 0.30). Among smokers in preparation, 21.1 % of proactive care participants achieved 6-month prolonged abstinence, compared to 13.1 % of usual care participants (OR, 1.8 [95 % CI, 1.2–2.6]). Similarly, proactive care increased abstinence among smokers in contemplation (11.0 % vs. 6.5 %; OR, 1.8 [95 % CI, 1.1–2.8]). Smokers in precontemplation quit smoking at similar rates (5.3 % vs. 5.6 %; OR, 0.9 [95 % CI, 0.5–1.9]). Within each stage, uptake of smoking cessation treatments increased with higher SOC and with proactive care as compared with usual care.LimitationsMostly male participants limits generalizability. Randomization was not stratified by SOC.ConclusionsProactive care increased treatment uptake compared to usual care across all SOC. Proactive care increased smoking cessation among smokers in preparation and contemplation but not in precontemplation. Proactively offering cessation therapies to smokers at all SOC will increase treatment utilization and population-level smoking cessation.

Disparities in the control of hypertension and other cardiovascular disease risk factors are well-documented in the United States, even among patients seen regularly in the healthcare system. Few existing approaches explicitly address disparities in hypertension care and control. This paper describes the RICH LIFE Project (Reducing Inequities in Care of Hypertension: Lifestyle Improvement for Everyone) design. RICH LIFE is a two-arm, cluster-randomized trial, comparing the effectiveness of enhanced standard of care, “Standard of Care Plus” (SCP), to a multi-level intervention, “Collaborative Care/Stepped Care” (CC/SC), for improving blood pressure (BP) control and patient activation and reducing disparities in BP control among 1890 adults with uncontrolled hypertension and at least one other cardiovascular disease risk factor treated at 30 primary care practices in Maryland and Pennsylvania. Fifteen practices randomized to the SCP arm receive standardized BP measurement training; race/ethnicity-specific audit and feedback of BP control rates; and quarterly webinars in management practices, quality improvement and disparities reduction. Fifteen practices in the CC/SC arm receive the SCP interventions plus implementation of the collaborative care model with stepped-care components (community health worker referrals and virtual specialist-panel consults). The primary clinical outcome is BP control (<140/90 mm Hg) at 12 months. The primary patient-reported outcome is change from baseline in self-reported patient activation at 12 months. This study will provide knowledge about the feasibility of leveraging existing resources in routine primary care and potential benefits of adding supportive community-facing roles to improve hypertension care and reduce disparities. Clinicaltrials.govNCT02674464