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As a method of research, pragmatic trials are recommended so as to generate results that are applicable to real-world care. This intent is especially important for the millions of older adults who receive long-term care in thousands of nursing homes and assisted living communities across the country-and many millions more around the globe. This article presents key points raised by experts participating in a conference funded by the National Institute of Aging held at the 2021 conference of the Society for Post-Acute and Long-term Care Medicine. The purpose of the conference was to convene leading clinicians, researchers, and industry partners to address special considerations of pragmatic trials in long-term care. Cross-cutting and unique challenges and solutions to conducting pragmatic trials were discussed focusing on 3 areas of clinical relevance to long-term care: (1) functional care and outcomes, (2) psychosocial care and quality of life, and (3) medical care and outcomes, with a special focus on persons with dementia. Challenges and innovative solutions were organized across the 9 domains of the revised Pragmatic-Explanatory Continuum Indicator Summary (PRECIS) Tool, and future research recommendations for pragmatic trials in long-term care were identified.

Background/Aims When participants in individually randomized group treatment trials are treated by multiple clinicians or in multiple group treatment sessions throughout the trial, this induces partially nested clusters which can affect the power of a trial. We investigate this issue in the Whole Health Options and Pain Education trial, a three-arm pragmatic, individually randomized clinical trial. We evaluate whether partial clusters due to multiple visits delivered by different clinicians in the Whole Health Team arm and dynamic participant groups due to changing group leaders and/or participants across treatment sessions during treatment delivery in the Primary Care Group Education arm may impact the power of the trial. We also present a Bayesian approach to estimate the intraclass correlation coefficients. Methods We present statistical models for each treatment arm of Whole Health Options and Pain Education trial in which power is estimated under different intraclass correlation coefficients and mapping matrices between participants and clinicians or treatment sessions. Power calculations are based on pairwise comparisons. In practice, sample size calculations depend on estimates of the intraclass correlation coefficients at the treatment sessions and clinician levels. To accommodate such complexities, we present a Bayesian framework for the estimation of intraclass correlation coefficients under different participant-to-session and participant-to-clinician mapping scenarios. We simulated continuous outcome data based on various clinical scenarios in Whole Health Options and Pain Education trial using a range of intraclass correlation coefficients and mapping matrices and used Gibbs samplers with conjugate priors to obtain posteriors of the intraclass correlation coefficients under those different scenarios. Posterior means and medians and their biases are calculated for the intraclass correlation coefficients to evaluate the operating characteristics of the Bayesian intraclass correlation coefficient estimators. Results Power for Whole Health Team versus Primary Care Group Education is sensitive to the intraclass correlation coefficient in the Whole Health Team arm. In these two arms, an increased number of clinicians, more evenly distributed workload of clinicians, or more homogeneous treatment group sizes leads to increased power. Our simulation study for the intraclass correlation coefficient estimation indicates that the posterior mean intraclass correlation coefficient estimator has less bias when the true intraclass correlation coefficients are large (i.e. 0.10), but when the intraclass correlation coefficient is small (i.e. 0.01), the posterior median intraclass correlation coefficient estimator is less biased. Conclusion Knowledge of intraclass correlation coefficients and the structure of clustering are critical to the design of individually randomized group treatment trials with partially nested clusters. We demonstrate that the intraclass correlation coefficient of the Whole Health Team arm can affect power in the Whole Health Options and Pain Education trial. A Bayesian approach provides a flexible procedure for estimating the intraclass correlation coefficients under complex scenarios. More work is needed to educate the research community about the individually randomized group treatment design and encourage publication of intraclass correlation coefficients to help inform future trial designs.

Background Serious illness conversations (SICs) are an evidence-based approach to eliciting patients’ values, goals, and care preferences that improve patient outcomes. However, most patients with cancer die without a documented SIC. Clinician-directed implementation strategies informed by behavioral economics (“nudges”) that identify high-risk patients have shown promise in increasing SIC documentation among clinicians. It is unknown whether patient-directed nudges that normalize and prime patients towards SIC completion—either alone or in combination with clinician nudges that additionally compare performance relative to peers—may improve on this approach. Our objective is to test the effect of clinician- and patient-directed nudges as implementation strategies for increasing SIC completion among patients with cancer. Methods We will conduct a 2 × 2 factorial, cluster randomized pragmatic trial to test the effect of nudges to clinicians, patients, or both, compared to usual care, on SIC completion. Participants will include 166 medical and gynecologic oncology clinicians practicing at ten sites within a large academic health system and their approximately 5500 patients at high risk of predicted 6-month mortality based on a validated machine-learning prognostic algorithm. Data will be obtained via the electronic medical record, clinician survey, and semi-structured interviews with clinicians and patients. The primary outcome will be time to SIC documentation among high-risk patients. Secondary outcomes will include time to SIC documentation among all patients (assessing spillover effects), palliative care referral among high-risk patients, and aggressive end-of-life care utilization (composite of chemotherapy within 14 days before death, hospitalization within 30 days before death, or admission to hospice within 3 days before death) among high-risk decedents. We will assess moderators of the effect of implementation strategies and conduct semi-structured interviews with a subset of clinicians and patients to assess contextual factors that shape the effectiveness of nudges with an eye towards health equity. Discussion This will be the first pragmatic trial to evaluate clinician- and patient-directed nudges to promote SIC completion for patients with cancer. We expect the study to yield insights into the effectiveness of clinician and patient nudges as implementation strategies to improve SIC rates, and to uncover multilevel contextual factors that drive response to these strategies. Trial registration ClinicalTrials.gov, NCT04867850. Registered on April 30, 2021. Funding National Cancer Institute P50CA244690

BackgroundFalls are common in older adults and can lead to severe injuries. The Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) trial cluster-randomized 86 primary care practices across 10 health systems to a multifactorial intervention to prevent fall injuries, delivered by registered nurses trained as falls care managers, or enhanced usual care. STRIDE enrolled 5451 community-dwelling older adults age ≥70 at increased fall injury risk.MethodsWe assessed fall-related outcomes via telephone interviews of participants (or proxies) every 4 months. At baseline, 12 and 24 months, we assessed health-related quality of life (HRQOL) using the EQ-5D-5L and EQ-VAS. We used Poisson models to assess intervention effects on falls, fall-related fractures, fall injuries leading to hospital admission, and fall injuries leading to medical attention. We used hierarchical longitudinal linear models to assess HRQOL.ResultsFor recurrent event models, intervention versus control incidence rate ratios were 0.97 (95% confidence interval [CI], 0.93-1.00; p= 0.048) for falls, 0.93 (95% CI, 0.80-1.08; p= 0.337) for self-reported fractures, 0.89 (95% CI, 0.73-1.07; p= 0.205) for adjudicated fractures, 0.91 (95% CI, 0.77-1.07; p= 0.263) for falls leading to hospital admission, and 0.97 (95% CI, 0.89-1.06; p= 0.477) for falls leading to medical attention. Similar effect sizes (non-significant) were obtained for dichotomous outcomes (e.g., participants with ≥1 events). The difference in least square mean change over time in EQ-5D-5L (intervention minus control) was 0.009 (95% CI, -0.002 to 0.019; p= 0.106) at 12 months and 0.005 (95% CI, -0.006 to 0.015; p= 0.384) at 24 months.ConclusionsAcross a standard set of outcomes typically reported in fall prevention studies, we observed modest improvements, one of which was statistically significant. Future work should focus on patient-, practice-, and organization-level operational strategies to increase the real-world effectiveness of interventions, and improving the ability to detect small but potentially meaningful clinical effects.Clinicaltrialsgov identifier: NCT02475850.

Background Routine evidence-based tobacco use treatment minimizes cancer-specific and all-cause mortality, reduces treatment-related toxicity, and improves quality of life among patients receiving cancer care. Few cancer centers employ mechanisms to systematically refer patients to evidence-based tobacco cessation services. Implementation strategies informed by behavioral economics can increase tobacco use treatment engagement within oncology care. Methods A four-arm cluster-randomized pragmatic trial will be conducted across nine clinical sites within the Implementation Science Center in Cancer Control Implementation Lab to compare the effect of behavioral economic implementation strategies delivered through embedded messages (or “nudges”) promoting patient engagement with the Tobacco Use Treatment Service (TUTS). Nudges are electronic medical record (EMR)-based messages delivered to patients, clinicians, or both, designed to counteract known patient and clinician biases that reduce treatment engagement. We used rapid cycle approaches (RCA) informed by relevant stakeholder experiences to refine and optimize our implementation strategies and methods prior to trial initiation. Data will be obtained via the EMR, clinician survey, and semi-structured interviews with a subset of clinicians and patients. The primary measure of implementation is penetration, defined as the TUTS referral rate. Secondary outcome measures of implementation include patient treatment engagement (defined as the number of patients who receive FDA-approved medication or behavioral counseling), quit attempts, and abstinence rates. The semi-structured interviews, guided by the Consolidated Framework for Implementation Research, will assess contextual factors and patient and clinician experiences with the nudges. Discussion This study will be the first in the oncology setting to compare the effectiveness of nudges to clinicians and patients, both head-to-head and in combination, as implementation strategies to improve TUTS referral and engagement. We expect the study to (1) yield insights into the effectiveness of nudges as an implementation strategy to improve uptake of evidence-based tobacco use treatment within cancer care, and (2) advance our understanding of the multilevel contextual factors that drive response to these strategies. These results will lay the foundation for how patients with cancer who smoke are best engaged in tobacco use treatment and may lead to future research focused on scaling this approach across diverse centers. Trial registration Clinicaltrials.gov, NCT04737031. Registered 3 February 2021.

Supplemental Digital Content is Available in the Text., Pragmatic randomised clinical trials aim to directly inform clinical or health policy decision making. Here, we systematically review methods and design of pragmatic trials of pain therapies to examine methods, identify common challenges, and areas for improvement. Seven databases were searched for pragmatic randomised controlled clinical trials that assessed pain treatment in a clinical population of adults reporting pain. All screening steps and data extractions were performed twice. Data were synthesised descriptively, and correlation analyses between prespecified trial features and PRECIS-2 (PRagmatic–Explanatory Continuum Indicator Summary 2) ratings and attrition were performed. Protocol registration: PROSPERO-ID CRD42020178954. Of 57 included trials, only 21% assessed pharmacological interventions, the remainder physical, surgical, psychological, or self-management pain therapies. Three-quarters of the trials were comparative effectiveness designs, often conducted in multiple centres (median: 5; Q1/3: 1, 9.25) and with a median sample size of 234 patients at randomization (Q1/3: 135.5; 363.5). Although most trials recruited patients with chronic pain, reporting of pain duration was poor and not well described. Reporting was comprehensive for most general items, while often deficient for specific pragmatic aspects. Average ratings for pragmatism were highest for treatment adherence flexibility and clinical relevance of outcome measures. They were lowest for patient recruitment methods and extent of follow-up measurements and appointments. Current practice in pragmatic trials of pain treatments can be improved in areas such as patient recruitment and reporting of methods, analysis, and interpretation of data. These improvements will facilitate translatability to other real-world settings—the purpose of pragmatic trials.

Favourable regulatory assessments, liberal policy changes, new research centres and substantial commercial investment signal that psychedelic therapy is making a major comeback. Positive findings from modern trials are catalysing developments, but it is questionable whether current confirmatory trials are sufficient for advancing our understanding of safety and best practice. Here we suggest supplementing traditional confirmatory trials with pragmatic trials, real-world data initiatives and digital health solutions to better support the discovery of optimal and personalised treatment protocols and parameters. These recommendations are intended to help support the development of safe, effective and cost-efficient psychedelic therapy, which, given its history, is vulnerable to excesses of hype and regulation.

Background The translation of evidence from clinical trials into practice is complex. One approach to facilitating this translation is to consider the ‘implementability’ of trials as they are designed and conducted. Implementability of trials refers to characteristics of the design, execution and reporting of a late-phase clinical trial that can influence the capacity for the evidence generated by that trial to be implemented. On behalf of the Australian Clinical Trials Alliance (ACTA), the national peak body representing networks of clinician researchers conducting investigator-initiated clinical trials, we conducted a pragmatic literature review to develop a concept map of implementability. Methods Documents were included in the review if they related to the design, conduct and reporting of late-phase clinical trials; described factors that increased or decreased the capacity of trials to be implemented; and were published after 2009 in English. Eligible documents included systematic reviews, guidance documents, tools or primary studies (if other designs were not available). With an expert reference group, we developed a preliminary concept map and conducted a snowballing search based on known relevant papers and websites of key organisations in May 2019. Results Sixty-five resources were included. A final map of 38 concepts was developed covering the domains of validity, relevance and usability across the design, conduct and reporting of a trial. The concepts drew on literature relating to implementation science, consumer engagement, pragmatic trials, reporting, research waste and other fields. No single resource addressed more than ten of the 38 concepts in the map. Conclusions The concept map provides trialists with a tool to think through a range of areas in which practical action could enhance the implementability of their trials. Future work could validate the strength of the associations between the concepts identified and implementability of trials and investigate the effectiveness of steps to address each concept. ACTA will use this concept map to develop guidance for trialists in Australia. Trial registration This review did not include health-related outcomes and was therefore not eligible for registration in the PROSPERO register.

Background and Objective: The Trials within Cohorts design aims to reduce recruitment difficulties and disappointment bias in pragmatic trials. On cohort enrollment, broad informed consent for randomization is asked, after which cohort participants can be randomized to interventions or serve as controls without further notification. We evaluated patients' recollection, understanding, and acceptance of broad consent in a clinical oncology setting. Methods: We surveyed 610 patients with cancer participating in ongoing TwiCs; 482 patients (79%) responded, of which 312 patients shortly after cohort enrollment, 108 patients after randomization to an intervention (12-18 months after cohort enrollment), and a random sample of 62 cohort participants who had not been selected for interventions (1-6 months after cohort enrollment). Results: Shortly after providing cohort consent, 76% of patients (238/312) adequately remembered whether they had given broad consent for randomization. Of patients randomly offered interventions, 76% (82/108) remembered giving broad consent for randomization; 41% (44/108) understood they were randomly selected, 44% (48/108) were not interested in selection procedures, and 10% (11/108) did not understand selection was random. Among patients not selected for interventions, 42% (26/62) understood selection was random; 89% felt neutral regarding the scenario of "not being selected for an intervention while your data were being used in comparison with patients receiving interventions,"10% felt reassured (6/62) and 2% scared/insecure (2/62). Conclusion: Patients adequately remember giving broad consent for randomization shortly after cohort enrollment and after being offered an intervention, but recollection is lower in those never selected for interventions. Patients are acceptant of serving as control without further notifications. (c) 2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Although Evidence-based medicine (EBM) and Patient-centered medicine (PCM) are often perceived as two conflicting paradigms that speak the language of populations and the language of individuals, respectively, both share the common objective of improving the care of individual patients. As physicians should not practice an EBM that is away from the individual patient nor a PCM that is not based on the best available evidence, it is crucial to connect and combine both movements, promoting the fruitful and natural interaction between research and care. Achieving such interaction requires developing new individual-patient centric research methods. In this commentary, we propose an innovative clinical research design oriented to personalize point-of-care trials -integrating clinical research and medical care -through the incorporation of individual patients' preferences to build personalized research protocols. Building on the framework of N-of-1 studies, in "individual point-of-care trials,"each protocol could be personalized for each patient so that the therapeutic objectives, the outcome variables analyzed, and the (operationalization of the) compared interventions would be based not only on the clinical and biological characteristics of each patient but also on their individual preferences, goals, and values. If patient preferences are being progressively integrated into medical practice, it makes sense that they also are incorporated into clinical trials embedded in care delivery. The proposal to perform individual point of care trials may be an optimal way to combine EBM and PCM while preserving their foundational principles, and to ensure the connection between "personalized"and "personal"care. (c) 2020 Elsevier Inc. All rights reserved.

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.

Background Stepped wedge cluster randomized trials (SW-CRT) are increasingly used to evaluate new clinical programs, yet there is limited guidance on practical aspects of applying this design. We report our early experiences conducting a SW-CRT to examine an inpatient mobility program (STRIDE) in the Veterans Health Administration (VHA). We provide recommendations for future research using this design to evaluate clinical programs. Methods Based on data from study records and reflections from the investigator team, we describe and assess the design and initial stages of a SW-CRT, from site recruitment to program launch in 8 VHA hospitals. Results Site recruitment consisted of thirty 1-h conference calls with representatives from 22 individual VAs who expressed interest in implementing STRIDE. Of these, 8 hospitals were enrolled and randomly assigned in two stratified blocks (4 hospitals per block) to a STRIDE launch date. Block 1 randomization occurred in July 2017 with first STRIDE launch in December 2017; block 2 randomization occurred in April 2018 with first STRIDE launch in January 2019. The primary study outcome of discharge destination will be assessed using routinely collected data in the electronic health record (EHR). Within randomized blocks, two hospitals per sequence launched STRIDE approximately every 3 months with primary outcome assessment paused during the 3-month time period of program launch. All sites received 6–8 implementation support calls, according to a pre-specified schedule, from the time of recruitment to program launch, and all 8 sites successfully launched within their assigned 3-month window. Seven of the eight sites initially started with a limited roll out (for example on one ward) or modified version of STRIDE (for example, using existing staff to conduct walks until new positions were filled). Conclusions Future studies should incorporate sufficient time for site recruitment and carefully consider the following to inform design of SW-CRTs to evaluate rollout of a new clinical program: (1) whether a blocked randomization fits study needs, (2) the amount of time and implementation support sites will need to start their programs, and (3) whether clinical programs are likely to include a “ramp-up” period. Successful execution of SW-CRT designs requires both adherence to rigorous design principles and also careful consideration of logistical requirements for timing of program roll out. Trial registration ClinicalsTrials.gov NCT03300336. Prospectively registered on 3 October 2017.

The current separation between medical research and care is an obstacle to essential aspects of good medical practice: the verification that care interventions actually deliver the good outcomes they promise, and the use of scientific methods to optimize care under uncertainty. Pragmatic care trials have been designed to address these problems. Care trials are all-inclusive randomized trials integrated into care. Every item of trial design is selected in the best medical interest of participating patients. Care trials can eventually show what constitutes good medical practice based on patient outcomes. In the meantime, care trials give clinicians and patients the scientific methods necessary for optimization of medical care when no one really knows what to do. We report the progress of 9 randomized care trials that were used to guide the endovascular or surgical management of 1212 patients with acute stroke, intracranial aneurysms, and arteriovenous malformations in a single center in an elective or acute care context. Care trials were used to address long-standing dilemmas regarding rival medical, surgical, or endovascular management options or to offer innovative instead of standard treatments. The trial methodology, by replacing unrepeatable treatment decisions by 1:1 randomized allocation whenever reliable knowledge was not available, had an immediate impact, transforming unverifiable dogmatic medical practice into verifiable outcome-based medical care. We believe the approach is applicable to all medical or surgical domains, but widespread adoption may require the revision of many currently prevalent views regarding the role of research in clinical practice.

Background Veterans Affairs (VA) has rolled out a holistic, multicomponent Whole Health care model nationwide, yet no pragmatic trials have been conducted in real-world clinical settings to compare its effectiveness against other evidence-based approaches for chronic pain management in veterans. Objectives We describe the adaptation of the first large pragmatic randomized controlled trial of the Whole Health model for chronic pain care for diverse VA clinical settings. Research design Informed by the Promoting Action on Research Implementation in Health Systems implementation framework, we conducted qualitative semistructured interviews to obtain feedback on trial design from VA leadership, frontline clinicians, and veterans with chronic pain at 5 VA enrollment sites. Next, we convened in-person evidence-based quality improvement (EBQI) meetings with study stakeholders (including frontline clinicians and administrators) at each site to discuss study design; review interview themes; and identify site-specific barriers, facilitators, and approaches to implementation. Ethnographic observations from EBQI meetings provided additional insight into implementation strategies. Subjects Seventy-four veteran and VA staff stakeholders were interviewed; 71 stakeholders participated in EBQI meetings. Results At each site, unique clinical contexts and varying resources for Whole Health and pain care delivery affected plans for trial implementation. We present examples of local adaptations that emerged through the formative evaluation process to facilitate implementation and yield a more pragmatic trial design. Conclusions A systematic formative evaluation can facilitate engagement and buy-in of study stakeholders. Locally tailored pragmatic implementation strategies may improve the likelihood of successful trial execution as well as future implementation of evidence-based pain care approaches in real-world clinical settings.

Background: Novel rationales for randomizing clusters rather than individuals appear to be emerging from the push for more pragmatic trials, for example, to facilitate trial recruitment, reduce the costs of research, and improve external validity. Such rationales may be driven by a mistaken perception that choosing cluster randomization lessens the need for informed consent. We reviewed a random sample of published cluster randomized trials involving only individual-level health care interventions to determine (a) the prevalence of reporting a rationale for the choice of cluster randomization; (b) the types of explicit, or if absent, apparent rationales for the use of cluster randomization; (c) the prevalence of reporting patient informed consent for study interventions; and (d) the types of justifications provided for waivers of consent. We considered cluster randomized trials for evaluating exclusively the individual-level health care interventions to focus on clinical trials where individual randomization is only theoretically possible and where there is a general expectation of informed consent. Methods: A random sample of 40 cluster randomized trials were identified by implementing a validated electronic search filter in two electronic databases (Ovid MEDLINE and Embase), with two reviewers independently extracting information from each trial. Inclusion criteria were the following: primary report of a cluster randomized trial, evaluating exclusively an individual-level health care intervention, published between 2007 and 2016, and conducted in Canada, the United States, European Union, Australia, or low- and middle-income country settings. Results: Twenty-five trials (62.5%, 95% confidence interval = 47.5%–77.5%) reported an explicit rationale for the use of cluster randomization. The most commonly reported rationales were those with logistical or administrative convenience (15 trials, 60%) and those that need to avoid contamination (13 trials, 52%); five trials (20%) were cited rationales related to the push for more pragmatic trials. Twenty-one trials (52.5%, 95% confidence interval = 37%–68%) reported written informed consent for the intervention, two (5%) reported verbal consent, and eight (20%) reported waivers of consent, while in nine trials (22.5%) consent was unclear or not mentioned. Reported justifications for waivers of consent included that study interventions were already used in clinical practice, patients were not randomized individually, and the need to facilitate the pragmatic nature of the trial. Only one trial reported an explicit and appropriate justification for waiver of consent based on minimum criteria in international research ethics guidelines, namely, infeasibility and minimal risk. Conclusion: Rationales for adopting cluster over individual randomization and for adopting consent waivers are emerging, related to the need to facilitate pragmatic trials. Greater attention to clear reporting of study design rationales, informed consent procedures, as well as justification for waivers is needed to ensure that such trials meet appropriate ethical standards.

OBJECTIVES The Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) study is testing the effectiveness of a multifactorial intervention to prevent serious fall injuries. Our aim was to describe procedures that were implemented to optimize participant retention; report retention yields by age, sex, clinical site, and follow-up time; provide reasons for study withdrawals; and highlight the successes and lessons learned from the STRIDE retention efforts. DESIGN Pragmatic cluster randomized trial. SETTING A total of 86 primary care practices within 10 US healthcare systems. PARTICIPANTS A total of 5451 community-living persons, 70 years of age or older, at high risk for serious fall injuries. MEASUREMENTS Study outcomes were collected every 4 months by a central call center. Reconsent was required to extend follow-up beyond the originally planned 36 months. RESULTS Over a median follow-up of 3.2 years (interquartile range = 2.8-3.7 y), 439 (8.1%) participants died and 600 (11.0%) withdrew their consent or did not reconsent to extend follow-up beyond 36 months, yielding rates (per 100 person-years) of deaths and withdrawals of 2.6 and 3.6, respectively. The withdrawal rate increased with advancing age, was comparable for men and women, and did not differ much by clinical site. The most common reasons for withdrawal were illness and unable to contact for reconsent at 36 months. Completion of the follow-up interviews was greater than 93% at each time point. Most participants completed all (71.8%) or all but one (9.2%) of the follow-up interviews. The most common reason for not completing a follow-up interview was unable to contact, with rates ranging from 2.8% at 40 months to 4.6% at 20 months. CONCLUSION Completion of the thrice-yearly follow-up interviews in STRIDE was high, and retention of participants over 44 months exceeded the original projections. The procedures used in STRIDE, together with lessons learned, should assist other investigators who are planning or conducting large pragmatic trials of vulnerable older persons. J Am Geriatr Soc 68:1242-1249, 2020.

Background The external validity of the randomized controlled trial (RCT) refers to the extent to which the results of the RCT apply to the relevant, non-trial population and is impacted by its eligibility criteria, its organization, and its delivery of the intervention. Here, we compared the outcomes of mortality and hospitalization between an RCT and a cohort study that concurrently enrolled HIV-exposed uninfected (HEU) newborns in Botswana. Methods The Mpepu Study (the RCT) was a clinical trial which determined that co-trimoxazole (CTX) provided no survival benefit for HEUs, allowing both arms of the RCT to be used. The Maikaelelo study (the cohort study) was a prospective observational study that enrolled HEU newborns with telephone follow-up and no in-person visits. Rates of death and hospitalization in the pooled population, were modeled using cox-proportional hazards models for time to death or time to first hospitalization, with study setting (RCT vs. cohort study) as an independent variable. The causal effect of study setting on morbidity and mortality was obtained through a treatment effects approach. Results In total, 4,010 infants were included; 1,306 were enrolled into the cohort study and 2,704 were enrolled into the RCT. No significant differences in mortality were observed between the two study settings (HR: 1.28, 95% CI: 0.76, 2.13), but RCT participants had a lower risk of hospitalization (HR: 0.72, 95% CI: 0.58, 0.89) that decreased with age. However, RCT participants had a higher risk of hospitalization within the first six months of life. The causal risk difference in hospitalizations attributable to the RCT setting was -0.03 (95% CI: -0.05, -0.01). Conclusions Children in an RCT with rigorous application of national standard of care guidelines experienced a significantly lower risk of hospitalization than children participating in a cohort study that did not alter clinical care. Future research is needed to further investigate outcome disparities when real-world results fail to mirror those achieved in a clinical trial. Trial registration The Mpepu Trial was funded by the U.S. National Institutes of Health (No. NCT01229761) and the Maikaelelo Study was funded primarily by the U.S. Centers for Disease Control and Prevention (32AI007433-21).

IntroductionChildren with chronic gastrointestinal symptoms are frequently seen in primary care, yet general practitioners (GPs) often experience challenges distinguishing functional gastrointestinal disorders (FGID) from organic disorders. We, therefore, aim to evaluate whether a test strategy that includes point-of-care testing (POCT) for faecal calprotectin (FCal) can reduce the referral rate to paediatric specialist care among children with chronic gastrointestinal symptoms. The study findings will contribute to improving the recommendations on FCal use among children in primary care.Methods and analysisIn this pragmatic cluster randomised controlled trial, we will randomise general practices into intervention and control groups. The intervention group will use FCal-POCT when indicated, after completing online training about its indication, interpretation and follow-up as well as communicating an FGID diagnosis. The control group will test and treat according to Dutch GP guidelines, which advise against FCal testing in children. GPs will include children aged 4–18 years presenting to primary care with chronic diarrhoea and/or recurrent abdominal pain. The primary outcome will be the referral rate for children with chronic gastrointestinal symptoms within 6 months after the initial assessment. Secondary outcomes will be evaluated by questionnaires completed at baseline and at 3- and 6-month follow-up. These outcomes will include parental satisfaction and concerns, gastrointestinal symptoms, impact of symptoms on daily function, quality of life, proportion of children with paediatrician-diagnosed FGID referred to secondary care, health service use and healthcare costs. A sample size calculation indicates that we need to recruit 158 GP practices to recruit 406 children.Ethics and disseminationThe Medical Research Ethics Committee (MREC) of the University Medical Center Groningen (The Netherlands) approved this study (MREC number: 201900309). The study results will be made available to patients, GPs, paediatricians and laboratories via peer-reviewed publications and in presentations at (inter)national conferences.Trial registration numberThe Netherlands Trial Register: NL7690 (Pre-results)

We resolve a controversy over two competing hypotheses about why people object to randomized experiments: 1) People unsurprisingly object to experiments only when they object to a policy or treatment the experiment contains, or 2) people can paradoxically object to experiments even when they approve of implementing either condition for everyone. Using multiple measures of preference and test criteria in five preregistered within-subjects studies with 1,955 participants, we find that people often disapprove of experiments involving randomization despite approving of the policies or treatments to be tested.

Objectives: This scoping review evaluates two decades of methodological advances made by “whole systems research” (WSR) pioneers in the fields of traditional, complementary, and integrative medicine (TCIM). Rooted in critiques of the classical randomized controlled trial (RCT)'s suitability for evaluating holistic, complex TCIM interventions, WSR centralizes the principle of “model validity,” representing a “fit” between research design and therapeutic paradigm. Design: In consultation with field experts, 41 clinical research exemplars were selected for review from across 13 TCIM disciplines, with the aim of mapping the range and methodological characteristics of WSR studies. Using an analytic charting approach, these studies' primary and secondary features are characterized with reference to three focal areas: research method, intervention design, and outcome assessment. Results: The reviewed WSR exemplars investigate a wide range of multimodal and multicomponent TCIM interventions, typified by wellness-geared, multitarget, and multimorbid therapeutic aims. Most studies include a behavioral focus, at times in multidisciplinary or team-based contexts. Treatments are variously individualized, often with reference to “dual” (biomedical and paradigm-specific) diagnoses. Prospective and retrospective study designs substantially reflect established biomedical research methods. Pragmatic, randomized, open label comparative effectiveness designs with “usual care” comparators are most widely used, at times with factorial treatment arms. Only two studies adopt a double-blind, placebo-controlled RCT format. Some cohort-based controlled trials engage nonrandomized allocation strategies (e.g., matched controls, preference-based assignment, and minimization); other key designs include single-cohort pre–post studies, modified n-of-1 series, case series, case report, and ethnography. Mixed methods designs (i.e., qualitative research and economic evaluations) are evident in about one-third of exemplars. Primary and secondary outcomes are predominantly assessed, at multiple intervals, through patient-reported measures for symptom severity, quality of life/wellness, and/or treatment satisfaction; some studies concurrently evaluate objective outcomes. Conclusions: Aligned with trends emphasizing “fit-for-purpose” research designs to study the “real-world” effectiveness of complex, personalized clinical interventions, WSR has emerged as a maturing scholarly discipline. The field is distinguished by its patient-centered salutogenic focus and engagement with nonbiomedical diagnostic and treatment frameworks. The rigorous pursuit of model validity may be further advanced by emphasizing complex analytic models, paradigm-specific outcome assessment, inter-rater reliability, and ethnographically informed designs. Policy makers and funders seeking to support best practices in TCIM research may refer to this review as a key resource.

Pragmatic trials testing the effectiveness of interventions under “real world” conditions help bridge the research-to-practice gap. Such trial designs are optimal for studying the impact of implementation efforts, such as the effectiveness of integrated behavioral health clinicians in primary care settings. Formal pragmatic trials conducted in integrated primary care settings are uncommon, making it difficult for researchers to anticipate the potential pitfalls associated with balancing scientific rigor with the demands of routine clinical practice. This paper is based on our experience conducting the first phase of a large, multisite, pragmatic clinical trial evaluating the implementation and effectiveness of behavioral health consultants treating patients with chronic pain using a manualized intervention, brief cognitive behavioral therapy for chronic pain (BCBT-CP). The paper highlights key choice points using the PRagmatic-Explanatory Continuum Indicator Summary (PRECIS-2) tool. We discuss the dilemmas of pragmatic research that we faced and offer recommendations for aspiring integrated primary care pragmatic trialists.

Digital health applications promise to improve patient health and medical care. This analysis provides a brief overview of evidence-based benefit assessment and the challenges to the underlying evidence as prerequisites for optimal patient-oriented decision making. Classical concepts in study design, recent developments, and innovative approaches are described with the aim of highlighting future areas of development in innovative study designs and strategic evaluation concepts for digital health applications. A special focus is on pragmatic study designs.Evidence-based benefit assessment has fundamental requirements and criteria regardless of the type of treatments evaluated. Reliable evidence is essential. Fast, efficient, reliable, and practice-relevant evaluation of digital health applications is not achieved by turning to nonrandomized trials, but rather by better pragmatic randomized trials. They are feasible and combine the characteristics of digital health applications, classical methodological concepts, and new approaches to study conduct. Routinely collected data, low-contact study conduct (remote trials, virtual trials), and digital biomarkers promote useful randomized real-world evidence as solid evidence base for digital health applications. Continuous learning evaluation with randomized designs embedded in routine care is key to sustainable and efficient benefit assessment of digital health applications and may be crucial for strategic improvement of healthcare.Digitale Gesundheitsanwendungen (DiGA) versprechen, die Gesundheit und medizinische Versorgung von Patienten zu verbessern. Dieser Beitrag gibt eine kurze Übersicht zur evidenzbasierten Nutzenbewertung und den Herausforderungen an die zugrunde liegende Evidenz als Voraussetzungen für eine optimale, patientenorientierte Entscheidungsfindung. Es werden klassische Konzepte des Studiendesigns, aktuelle Entwicklungen und innovative Ansätze beschrieben mit dem Ziel, zukünftige Entwicklungsfelder für innovative Studiendesigns und strategische Evaluationskonzepte für DiGA aufzuzeigen. Ein besonderer Schwerpunkt liegt auf der Anwendung pragmatischer Studiendesigns.Evidenzbasierte Nutzenbewertung hat fundamentale Anforderungen und Maßstäbe unabhängig von der Art der evaluierten Behandlungen. Zuverlässige Evidenz ist unverzichtbar. Eine schnelle, effiziente, zuverlässige und praxisrelevante Evaluation von DiGA gelingt nicht durch eine Hinwendung zu nichtrandomisierten Studien, sondern vielmehr durch bessere, pragmatische randomisierte Studien. Sie sind machbar und verbinden die Charakteristika von DiGA, klassische methodische Konzepte und neue Ansätze der Studiendurchführung. Routinedaten, kontaktarme Studiendurchführung („virtual trials“, „remote trials“) und digitale Biomarker fördern nützliche randomisierte Real-World-Evidenz als solide Evidenzbasis von DiGA. Eine kontinuierliche, lernende Evaluation im Versorgungsalltag mit in die Routine eingebetteten randomisierten Studiendesigns ist der Schlüssel zur nachhaltigen und effizienten Nutzenbewertung von DiGA und kann entscheidend für eine strategische Verbesserung der Gesundheitsversorgung sein.

Background Chronic diseases that drive morbidity, mortality, and health care costs are largely influenced by human behavior. Behavioral health conditions such as anxiety, depression, and substance use disorders can often be effectively managed. The majority of patients in need of behavioral health care are seen in primary care, which often has difficulty responding. Some primary care practices are providing integrated behavioral health care (IBH), where primary care and behavioral health providers work together, in one location, using a team-based approach. Research suggests there may be an association between IBH and improved patient outcomes. However, it is often difficult for practices to achieve high levels of integration. The Integrating Behavioral Health and Primary Care study responds to this need by testing the effectiveness of a comprehensive practice-level intervention designed to improve outcomes in patients with multiple chronic medical and behavioral health conditions by increasing the practice’s degree of behavioral health integration. Methods Forty-five primary care practices, with existing onsite behavioral health care, will be recruited for this study. Forty-three practices will be randomized to the intervention or usual care arm, while 2 practices will be considered “Vanguard” (pilot) practices for developing the intervention. The intervention is a 24-month supported practice change process including an online curriculum, a practice redesign and implementation workbook, remote quality improvement coaching services, and an online learning community. Each practice’s degree of behavioral health integration will be measured using the Practice Integration Profile. Approximately 75 patients with both chronic medical and behavioral health conditions from each practice will be asked to complete a series of surveys to measure patient-centered outcomes. Change in practice degree of behavioral health integration and patient-centered outcomes will be compared between the two groups. Practice-level case studies will be conducted to better understand the contextual factors influencing integration. Discussion As primary care practices are encouraged to provide IBH services, evidence-based interventions to increase practice integration will be needed. This study will demonstrate the effectiveness of one such intervention in a pragmatic, real-world setting. Trial registration ClinicalTrials.gov NCT02868983. Registered on August 16, 2016.

Background Pragmatic trials often consist of cluster-randomized controlled trials (C-RCTs), where staff of existing clinics or sites deliver interventions and randomization occurs at the site level. Covariate-constrained randomization (CCR) methods are often recommended to minimize imbalance on important site characteristics across intervention and control arms because sizable imbalances can occur by chance in simple randomizations when the number of units to be randomized is relatively small. CCR methods involve multiple random assignments initially, an assessment of balance achieved on site-level covariates from each randomization, and the final selection of an allocation that produces acceptable balance. However, no clear consensus exists on how to assess imbalance or identify allocations with sufficient balance. In this article, we describe an overall imbalance index (I) that is based on the mean of the absolute value of the standardized differences in means on the site characteristics. Methods We derive the theoretical distribution of I, then conduct simulation studies to examine its empirical properties under the varying covariate distributions and inter-correlations. Results I has an expected value of 0.798 and, assuming independent site characteristics, a variance of 0.363/k, where k is the number of site characteristics being balanced. Simulations indicated that the properties of I are robust under varying covariate circumstances as long as k is greater than 3 and the covariates are not too highly inter-correlated. Conclusions We recommend that values of I below the 10th percentile indicate sufficient overall site balance in CCRs. Definitions of acceptable randomizations might also include individual covariate criteria specified in advance, in addition to overall balance criteria.

Author(s): Gill, Thomas M; Bhasin, Shalender; Reuben, David B; Latham, Nancy K; Araujo, Katy; Ganz, David A; Boult, Chad; Wu, Albert W; Magaziner, Jay; Alexander, Neil; Wallace, Robert B; Miller, Michael E; Travison, Thomas G; Greenspan, Susan L; Gurwitz, Jerry H; Rich, Jeremy; Volpi, Elena; Waring, Stephen C; Manini, Todd M; Min, Lillian C; Teresi, Jeanne; Dykes, Patricia C; McMahon, Siobhan; McGloin, Joanne M; Skokos, Eleni A; Charpentier, Peter; Basaria, Shehzad; Duncan, Pamela W; Storer, Thomas W; Gazarian, Priscilla; Allore, Heather G; Dziura, James; Esserman, Denise; Carnie, Martha B; Hanson, Catherine; Ko, Fred; Resnick, Neil M; Wiggins, Jocelyn; Lu, Charles; Meng, Can; Goehring, Lori; Fagan, Maureen; Correa-de-Araujo, Rosaly; Casteel, Carri; Peduzzi, Peter; Greene, Erich J | Abstract: Background/objectivesIn the Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) study, a multifactorial intervention was associated with a nonsignificant 8% reduction in time to first serious fall injury but a significant 10% reduction in time to first self-reported fall injury relative to enhanced usual care. The effect of the intervention on other outcomes important to patients has not yet been reported. We aimed to evaluate the effect of the intervention on patient well-being including concern about falling, anxiety, depression, physical function, and disability.DesignPragmatic cluster-randomized trial of 5,451 community-living persons at high risk for serious fall injuries.SettingA total of 86 primary care practices within 10 U.S. healthcare systems.ParticipantsA random subsample of 743 persons aged 75 and older.MeasurementsThe well-being measures, assessed at baseline, 12 months, and 24 months, included a modified version of the Fall Efficacy Scale, Patient-Reported Outcomes Measurement Information System (PROMIS) anxiety and depression scales, and Late-Life Function and Disability Instrument.ResultsParticipants in the intervention (n = 384) and control groups (n = 359) were comparable in age: mean (standard deviation) of 81.9 (4.7) versus 81.8 (5.0) years. Mean scores were similar between groups at 12 and 24 months for concern about falling, physical function, and disability, whereas the intervention group's mean scores on anxiety and depression were .7 points lower (i.e., better) at 12 months and .6 to .8 points lower at 24 months. For each of these outcomes, differences between the groups' adjusted least square mean changes from baseline to 12 and 24 months, respectively, were quantitatively small. The overall difference in means between groups over 2 years was statistically significant only for depression, favoring the intervention: -1.19 (99% confidence interval, -2.36 to -.02), with 3.5 points representing a minimally important difference.ConclusionsSTRIDE's multifactorial intervention to reduce fall injuries was not associated with clinically meaningful improvements in patient well-being.

Background First articulated by Schwartz and Lellouch (1967), randomized controlled trials (RCTs) can be conceptualized along a continuum from more explanatory to more pragmatic. The purpose and intent of the former is to test interventions under ideal contexts, and the purpose and intent of the latter is to test interventions in real-world contexts. The PRagmatic Explanatory Continuum Indicator Summary-2 (PRECIS-2) is a validated tool that helps researchers make decisions about the elements of the trial to match the overall purpose and intent of the trial along the continuum. The PRECIS-2 tool has guided the design of hundreds of RCTs. However, a few aspects of the tool would benefit from greater clarity, including its application to provider-focused implementation trials rather than patient-focused intervention trials. Main text We describe the newly developed PRECIS-2-Provider Strategies (PRECIS-2-PS) tool, an extension of the PRECIS-2 tool, which has been adapted for trials testing provider-focused strategies. We elaborate on nine domains that can make a provider-focused trial more explanatory or more pragmatic, including eligibility, recruitment, setting, implementation resources, flexibility of provider strategies, flexibility of intervention, data collection, primary outcome, and primary analysis. We detail the complementary roles that researchers and stakeholders play in the trial design phase, with implications for generalizability of trial results to the contexts in which they are intended to be applied. Conclusions The PRECIS-2-PS tool is designed to help research and practice teams plan for provider-focused trials that reflect the overall intent and purpose of the trial. The tool has potential to help advance the science of provider-focused strategies across a range of trials, with the ultimate goal of facilitating the adoption, integration, and sustainability of provider-focused strategies outside the context of trials.

Author(s): Reuben, David B; Gill, Thomas M; Stevens, Alan; Williamson, Jeff; Volpi, Elena; Lichtenstein, Maya; Jennings, Lee A; Tan, Zaldy; Evertson, Leslie; Bass, David; Weitzman, Lisa; Carnie, Martie; Wilson, Nancy; Araujo, Katy; Charpentier, Peter; Meng, Can; Greene, Erich J; Dziura, James; Liu, Jodi; Unger, Erin; Yang, Mia; Currie, Katherine; Lenoir, Kristin M; Green, Aval-NaʼRee S; Abraham, Sitara; Vernon, Ashley; Samper-Ternent, Rafael; Raji, Mukaila; Hirst, Roxana M; Galloway, Rebecca; Finney, Glen R; Ladd, Ilene; Rahm, Alanna Kulchak; Borek, Pamela; Peduzzi, Peter | Abstract: Background/objectivesAlthough several approaches have been developed to provide comprehensive care for persons living with dementia (PWD) and their family or friend caregivers, the relative effectiveness and cost effectiveness of community-based dementia care (CBDC) versus health system-based dementia care (CBDC) and the effectiveness of both approaches compared with usual care (UC) are unknown.DesignPragmatic randomized three-arm superiority trial. The unit of randomization is the PWD/caregiver dyad.SettingFour clinical trial sites (CTSs) based in academic and clinical health systems.ParticipantsA total of 2,150 English- or Spanish-speaking PWD who are not receiving hospice or residing in a nursing home and their caregivers.InterventionsEighteen months of (1) HSDC provided by a nurse practitioner or physician's assistant dementia care specialist who works within the health system, or (2) CBDC provided by a social worker or nurse care consultant who works at a community-based organization, or (3) UC with as needed referral to the Alzheimer's Association Helpline.MeasurementsPrimary outcomes: PWD behavioral symptoms and caregiver distress as measured by the Neuropsychiatric Inventory Questionnaire (NPI-Q) Severity and Modified Caregiver Strain Index scales.Secondary outcomesNPI-Q Distress, caregiver unmet needs and confidence, and caregiver depressive symptoms. Tertiary outcomes: PWD long-term nursing home placement rates, caregiver-reported PWD functional status, cognition, goal attainment, "time spent at home," Dementia Burden Scale-Caregiver, a composite measure of clinical benefit, Quality of Life of persons with dementia, Positive Aspects of Caregiving, and cost effectiveness using intervention costs and Medicare claims.ResultsThe results will be reported in the spring of 2024.ConclusionD-CARE will address whether emphasis on clinical support and tighter integration with other medical services has greater benefit than emphasis on social support that is tied more closely to community resources. It will also assess the effectiveness of both interventions compared with UC and will evaluate the cost effectiveness of each intervention.

Background Almost 20% of U.S. women remain at risk for cervical cancer due to their inability or unwillingness to participate in periodic clinic-based screening. Self-sampling has been shown to be an effective strategy for screening women for high-risk human papillomavirus (HR-HPV) infection in specific contexts. However, its effectiveness among medically underserved women in safety net health systems has not been evaluated. Furthermore, it is also unclear whether implementation strategies such as patient navigation can be used to improve the success of self-sample screening programs by addressing patient-level barriers to participation. Methods/design The Prospective Evaluation of Self-Testing to Increase Screening (PRESTIS) trial is a hybrid type 2 effectiveness-implementation pragmatic randomized controlled trial of mailed self-sample HPV testing. The aim is to assess the effectiveness of mailed self-sample HPV testing kits to improve cervical cancer screening participation among patients in a safety net health system who are overdue for clinic-based screening, while simultaneously assessing patient navigation as an implementation strategy. Its setting is a large, urban safety net health system that serves a predominantly racial/ethnic minority patient population. The trial targets recruitment of 2268 participants randomized to telephone recall (enhanced usual care, n = 756), telephone recall with mailed self-sample HPV testing kit (intervention, n = 756), or telephone recall with mailed self-sample HPV testing kit and patient navigation (intervention + implementation strategy, n = 756). The primary effectiveness outcome is completion of primary screening, defined as completion and return of mailed self-sample kit or completion of a clinic-based Pap test. Secondary effectiveness outcomes are predictors of screening and attendance for clinical follow-up among women with a positive screening test. Implementation outcomes are reach, acceptability, fidelity, adaptations, and cost-effectiveness. Discussion Hybrid designs are needed to evaluate the clinical effectiveness of self-sample HPV testing in specific populations and settings, while incorporating and evaluating methods to optimize its real-world implementation. The current manuscript describes the rationale and design of a hybrid type 2 trial of self-sample HPV testing in a safety net health system. Trial findings are expected to provide meaningful data to inform screening strategies to ultimately realize the global goal of eliminating cervical cancer. Trial registration ClinicalTrials.gov NCT03898167. Registered on 01 April 2019. Trial status Study start data: February 13, 2020. Recruitment status: Enrolling by invitation. Estimated primary completion date: February 15, 2023. Estimated study completion date: May 31, 2024. Protocol version 1.6 (February 25, 2020).

Starting from historic reflections, the current SARS-CoV-2 induced COVID-19 pandemic is examined from various perspectives, in terms of what it implies for the implementation of non-pharmaceutical interventions, the modeling and monitoring of the epidemic, the development of early-warning systems, the study of mortality, prevalence estimation, diagnostic and serological testing, vaccine development, and ultimately clinical trials. Emphasis is placed on how the pandemic had led to unprecedented speed in methodological and clinical development, the pitfalls thereof, but also the opportunities that it engenders for national and international collaboration, and how it has simplified and sped up procedures. We also study the impact of the pandemic on clinical trials in other indications. We note that it has placed biostatistics, epidemiology, virology, infectiology, and vaccinology, and related fields in the spotlight in an unprecedented way, implying great opportunities, but also the need to communicate effectively, often amidst controversy. Buyse, M (corresponding author), Hasselt Univ, Interuniv Inst Biostat & Stat Bioinformat, Data Sci Inst, Martelarenlaan 42, Hasselt, Belgium. marc.buyse@iddi.com

Background Chinese guidelines for the treatment of type 2 diabetes (T2D) recommend basal or premixed insulins as insulin starters after failed oral antihyperglycaemic medication (OAM). This pragmatic study compared effectiveness and safety of add‐on basal insulin analog (BI) and mid‐mixture insulin analog (MMI; 50:50 premixed insulin) as starter insulin regimens in Chinese patients with T2D in a real‐world setting. Materials and Methods This was a multicentre, open‐label, randomized, parallel, pragmatic trial. Patients receiving OAMs were randomized 1:1 to BI (n = 410) or MMI (n = 404) for 24 weeks. Insulin titration and OAM adjustment were determined by investigators following usual standard‐of‐care. The primary outcome was change in glycated haemoglobin (HbA1c) from baseline. Results Least‐squares mean changes in HbA1c from baseline to week 24 were −2.00% and −2.15% for BI and MMI groups, respectively (P = .13). The MMI group demonstrated a greater reduction in concomitant OAM therapies used than BI group (53.8% vs. 35.3%, respectively; P

Aims Pragmatic randomized clinical trials (pRCTs) collect data that have the potential to improve medical care significantly. However, these trials may be undermined by the requirement to obtain written informed consent, which can decrease accrual and increase selection bias. Recent data suggest that the majority of the US public endorses written consent for low‐risk pRCTs. The present study was designed to assess whether this view is specific to the US. Methods The study took the form of a cross‐sectional, probability‐based survey, with a 2 × 2 factorial design, assessing support for written informed consent vs. verbal consent or general notification for two low‐risk pRCTs in hypertension, one comparing two drugs with similar risk/benefit profiles and the other comparing the same drug being taken in the morning or at night. The primary outcome measures were respondents' personal preference and hypothetical recommendation to a research ethics committee regarding the use of written informed consent vs. the alternatives. Results A total of 2008 adults sampled from a probability‐based online panel responded to the web‐based survey conducted in May 2016 (response rate: 61%). Overall, 77% of respondents endorsed written consent. In both scenarios, the alternative of general notification received significantly more support (28.7–37.1%) than the alternative of verbal consent (12.7–14.0%) (P = 0.001). Forty per cent of respondents preferred and/or recommended general notification rather than written consent. Conclusions The results suggested that, rather than attempting to waive written consent, current pRCTs should focus on developing ways to implement written consent that provide sufficient information without undermining recruitment or increasing selection bias. The finding that around 40% of respondents endorsed general notification over written consent raises the possibility that, with educational efforts, the majority of Spaniards might accept general notification for low‐risk pRCTs.

Background Traditional randomised controlled trials remain the gold standard for improving clinical care but they do have their limitations, including their associated high costs, high failure rate and limited external validity. An alternative methodology is the newly defined, prospective, registry-based randomised controlled trial (RRCT), where treatment and outcome data is collected in an existing registry. This scoping review explores the current literature regarding RRCTs to help identify the key design elements of RRCTs and the characteristics of clinical registries on which they are reliant on. Methods A scoping review methodology conducted in accordance with the Joanna Briggs Institute guidelines was performed. Four databases were searched for articles published from inception to June 2018: Medline; Embase; the Cumulative Index to Nursing and Allied Health Literature and; Scopus. The search strategy included MeSH and text words related to RRCT. Results We identified 2369 articles of which 75 were selected for full-text screening. Of these, only 17 articles satisfied our inclusion criteria. All studies were published between 1996 and 2017 and all were investigator-initiated. Study designs were mainly multi-site comparative/effectiveness studies incorporating the use of disease registries (n = 8), procedure registries (n = 8) and a health services registry (n = 1). The low cost, reduced administrative burden and enhanced external validity of RRCTs make them an attractive research methodology which can be used to address questions of public health importance. We identified that that there are variable definitions of what constituted a RRCT and that issues related to ethical conduct and data integrity, completeness, timeliness, validation and endpoint adjudication need to be carefully addressed. Conclusion RRCTs potentially have an important role to play in informing best clinical practice and health policy. There are a number of issues that need to be addressed to optimise the utility of this approach, including establishing universally accepted criteria for the definition of a RRCT.

Background The paper opens with a brief history of two of the major intellectual components of the recent utilitarian turn in clinical research, namely ‘pragmatic trials’ and ‘implementation science’. The two schools of thought developed independently and the paper scrutinises their mutual compatibilities and incompatibilities, asking: i) what do the leading advocates of pragmatic trials assume about the transfer of research findings to real-world practice and ii) what role pragmatic trials can and should play in the evaluation of implementation science strategies. Methods The paper utilises ‘explication de texte’: i) providing a close reading of the inferential logics contained in major published expositions of the two paradigms, and ii) interrogating the conclusions of a pragmatic trial of an intervention providing guidelines on retinal screening aimed at family practitioners. Results The paper is in two parts. Part 1 unearths some significant incommensurability – the pragmatic trial literature retains an antiquated view of knowledge transfer and is overly optimistic about the wide applicability the findings of pragmatic trials to ‘real world’ conditions. Part 2 of the paper outlines an empirical strategy to better penetrate the mechanisms of knowledge transfer and to tackle the issue of the generalisabilty of research findings in implementation science. Conclusions Pragmatism, classically, is about problem solving and the melding of perspectives. The core research requirement in implementation science is a fundamental shift from the narrow shoulders of pragmatic trials to a model of explanation building based upon a multi-case, multi-method body of evidence.

Background Improving efficiencies in clinical research is crucial to translation of findings into practice and delivery of effective, patient-centered health care. This paper describes a project that monitored pragmatic clinical trials by working with investigators to track achievement of early phase milestones. The National Institutes of Health (NIH) Pragmatic Trials Collaborative Project supported scientifically diverse, low-cost, randomized, controlled, pragmatic clinical intervention trials. Funds were available through a cooperative agreement award mechanism, with the initial phase supporting trial planning and the subsequent 4-year awards funding trial implementation. A coordinating center provided evaluation and administrative support, which included capturing progress toward achieving milestones. Methods Six funded trials participated in monthly calls throughout the first year to identify and demonstrate metrics and deliverables for each milestone in the Notice of Grant Award. Interviews were conducted with investigators, trial team members, and NIH program officers/project scientists to discuss their perceptions of the impact and value of the management strategy. Results Five of six trials transitioned to the implementation phase with milestones ranging from 6 to 15 and quantifiable metrics ranging from 15 to 33, for a total of 121 deliverables. One third of the metrics (42, 35%) were trial-specific. Trial teams reported that the oversight was onerous but complemented their management strategies; program officers/project scientists found that documentation submitted for review was sufficient to assess trial feasibility; and investigators reported advantages to the phased award mechanism, such as leverage to secure commitments from stakeholders and collaborators, help with task prioritization, and earlier consultation with key members of the trial team. Conclusions Implementing systematic approaches to identify milestones and track metrics can strengthen the evidence base regarding time and effort to plan and conduct pragmatic clinical trials. Investigators were unaccustomed to producing evidence of performance, and it was challenging to determine what documentation to provide. Efforts to standardize expectations regarding milestones that mark a significant change or stage in trial development or that represent minimum success criteria may provide guidance for more effective and efficient trial management. A framework with clearly specified metrics is especially critical for transparency, particularly when funding decisions are contingent on both merit and feasibility.

BackgroundBuilding capacity in research funding organizations to support the conduct of pragmatic clinical trials is an essential component of advancing biomedical and public health research. To date, efforts to increase the ability to design and carry out pragmatic trials have largely focused on training researchers. To complement these efforts, we developed an interactive workshop tailored to meet the roles and responsibilities of program scientists at the National Cancer Institute—the leading cancer research funding agency in the USA. The objectives of the workshop were to improve the understanding of pragmatic trials and enhance the capacity to distinguish between elements that make a trial more pragmatic or more explanatory among key programmatic staff. To our knowledge, this is the first reported description of such a workshop.Main bodyThe workshop was developed to meet the needs of program scientists as researchers and stewards of research funds, which often includes promoting scientific initiatives, advising prospective applicants, collaborating with grantees, and creating training programs. The workshop consisted of presentations from researchers with expertise in the design and interpretation of trials across the explanatory-pragmatic continuum. Presentations were followed by interactive, small-group exercises to solidify participants’ understanding of the purpose and conduct of these trials, which were tailored to attendees’ areas of expertise across the cancer control continuum and designed to reflect their scope of work as program scientists at NCI. A total of 29 program scientists from the Division of Cancer Control and Population Sciences and the Division of Cancer Prevention participated; 19 completed a post-workshop evaluation. Attendees were very enthusiastic about the workshop: they reported improved knowledge, significant relevance of the material to their work, and increased interest in pragmatic trials across the cancer control continuum.ConclusionTraining program scientists at major biomedical research agencies who are responsible for developing funding opportunities and advising grantees is essential for increasing the quality and quantity of pragmatic trials. Together with workshops for other target audiences (e.g., academic researchers), this approach has the potential to shape the future of pragmatic trials and continue to generate more and better actionable evidence to guide decisions that are of critical importance to health care practitioners, policymakers, and patients.

Background: Randomised controlled trials provide the best evidence for the effects of interventions and are a key tool in the effort to improve the care and outcomes for newborn infants. Methods: We discuss the role of randomisation for minimising selection bias in clinical trials and describe examples of seminal trials that have shaped the development of modern perinatal care. We consider the challenges inherent in designing and delivering large, simple, and pragmatic trials, and the need for the development and adoption of core outcome sets to ensure that trials provide high-quality evidence of sufficient validity and applicability to guide policy and practice. Results: Since the earliest days of modern neonatology, the randomised controlled trial has been recognised as the best method for assessing treatments and practices. While many strategies that reduce mortality and morbidity have been introduced following randomised trials, there are, however, important examples of ineffective or potentially harmful practices that have been adopted in the absence of trial-based evidence. Typically, randomised controlled trials in perinatal care need to recruit several thousand participants to be able to detect modest but potentially important effects of new interventions on the most important but rare outcomes. Given the concerns about the financial burden and regulatory complexity of standard trial designs, innovative “efficient” trial designs are being evaluated to streamline processes while safeguarding participants. Conclusions: Well-conducted randomised controlled trials provide the most robust evaluation of interventions aimed at improving outcomes for newborn infants and their families. Increasingly, these trials will need to be large and multicentre (often international) and use a simple and pragmatic protocol, incorporating meticulous follow-up procedures and assessment of long-term outcomes.

Registry-based randomized controlled trials (RCTs) are presumed to include a less-selected patient population and thus to have enhanced generalizability compared to conventional RCTs. However, this view disregards the levels of patient selection in registry-based RCTs: the registry selection level and the trial selection level. At both levels, systematic selection can occur and generalizability can be diminished. Nevertheless, using a registry as a basis for recruitment, randomization, and data collection results in an advantage: the trial selection takes place within the registry framework, where baseline characteristics of non-enrolled patients are automatically documented as well. By comparing the baseline variables of the enrolled and non-enrolled patients, the trial selection can always be investigated, which gives a sound basis for discussing the generalizability to the registry population.

© 2019, Mary Ann Liebert, Inc. Introduction: Naturopathy is a mixture of both traditional and complementary medicine. It incorporates a broad set of health care practices that may or may not be traditional to that country or conventional medicine and are not fully integrated into the dominant health care system. Research required to evaluate or substantiate naturopathic medicine may not fall under the testing of randomized clinical trials, which opens up discussions on what is the best practice for research in naturopathic medicine. Discussion: Not only do advances in health research methodology offer important opportunities to progress naturopathic research, there are also areas where the unique characteristics of naturopathic philosophy and practice can impact other areas of health research. Some of the new advances in health research methodology involve whole-system research, pragmatic trials, template for intervention description and replication protocols for complex interventions, patient-centered care models, and the pragmatic-explanatory continuum indicator summary tool for designing pragmatic trials. Discussion and critique of these health-related methodologies shows that these research methods are more suited for the philosophy and treatment options that naturopathy is based on. Conclusions: Successful implementation of naturopathic research methodologies, and translation and dissemination of research will require a substantial paradigm shift in which naturopathic practitioners adopt a greater level of responsibility for developing an evidence base for naturopathic medicine.

Pragmatic randomized controlled trials (RCTs) mimic usual clinical practice and they are critical to inform decision-making by patients, clinicians and policy-makers in real-world settings. Pragmatic RCTs assess effectiveness of available medicines, while explanatory RCTs assess efficacy of investigational medicines. Explanatory and pragmatic are the extremes of a continuum. This debate article seeks to evaluate and provide recommendation on how to characterize pragmatic RCTs in light of the current landscape of RCTs. It is supported by findings from a PubMed search conducted in August 2017, which retrieved 615 RCTs self-labeled in their titles as "pragmatic" or "naturalistic". We focused on 89 of these trials that assessed medicines (drugs or biologics).36% of these 89 trials were placebo-controlled, performed before licensing of the medicine, or done in a single-center. In our opinion, such RCTs overtly deviate from usual care and pragmatism. It follows, that the use of the term 'pragmatic' to describe them, conveys a misleading message to patients and clinicians. Furthermore, many other trials among the 615 coined as 'pragmatic' and assessing other types of intervention are plausibly not very pragmatic; however, this is impossible for a reader to tell without access to the full protocol and insider knowledge of the trial conduct. The degree of pragmatism should be evaluated by the trial investigators themselves using the PRECIS-2 tool, a tool that comprises 9 domains, each scored from 1 (very explanatory) to 5 (very pragmatic).To allow for a more appropriate characterization of the degree of pragmatism in clinical research, submissions of RCTs to funders, research ethics committees and to peer-reviewed journals should include a PRECIS-2 tool assessment done by the trial investigators. Clarity and accuracy on the extent to which a RCT is pragmatic will help understand how much it is relevant to real-world practice.