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Journal of Clinical Epidemiology Sep 2022Methodologies incorporating Real World Elements into clinical trial design (also called pragmatic trials) offer an attractive opportunity to assess the effect of a...
Methodologies incorporating Real World Elements into clinical trial design (also called pragmatic trials) offer an attractive opportunity to assess the effect of a treatment strategy in routine care and as such guide decision making in practice. Uptake of these methods is slow for several reasons, including uncertainty about acceptability of trial results, lack of experience with the methodology and operational challenges. We developed the "GetReal Trial Tool," an easy-to-use online interface, which allows users to assess the impact of design choices on generalizability to routine clinical practice, while taking into account risk of bias, precision, acceptability and operational feasibility. The tool is grounded in the scientific literature combined with knowledge of experts from academia, pharmaceutical companies, HTA bodies, patient organizations, and regulators. The aim is to help researchers optimize trial design and facilitate translation of evidence from pragmatic trials to clinical practice. In this paper we describe the development, structure and application of the GetReal Trial Tool.
Topics: Humans; Data Collection; Drug Evaluation; Research Design; Research Personnel; Clinical Trials as Topic
PubMed: 34929319
DOI: 10.1016/j.jclinepi.2021.12.019 -
Clinical Trials (London, England) Oct 2015To successfully implement a pragmatic clinical trial, investigators need access to numerous resources, including financial support, institutional infrastructure (e.g....
To successfully implement a pragmatic clinical trial, investigators need access to numerous resources, including financial support, institutional infrastructure (e.g. clinics, facilities, staff), eligible patients, and patient data. Gatekeepers are people or entities who have the ability to allow or deny access to the resources required to support the conduct of clinical research. Based on this definition, gatekeepers relevant to the US clinical research enterprise include research sponsors, regulatory agencies, payers, health system and other organizational leadership, research team leadership, human research protections programs, advocacy and community groups, and clinicians. This article provides a framework to help guide gatekeepers' decision-making related to the use of resources for pragmatic clinical trials. Relevant ethical considerations for gatekeepers include (1) concern for the interests of individuals, groups, and communities affected by the gatekeepers' decisions, including protection from harm and maximization of benefits; (2) advancement of organizational mission and values; and (3) stewardship of financial, human, and other organizational resources. Separate from these ethical considerations, gatekeepers' actions will be guided by relevant federal, state, and local regulations. This framework also suggests that to further enhance the legitimacy of their decision-making, gatekeepers should adopt transparent processes that engage relevant stakeholders when feasible and appropriate. We apply this framework to the set of gatekeepers responsible for making decisions about resources necessary for pragmatic clinical trials in the United States, describing the relevance of the criteria in different situations and pointing out where conflicts among the criteria and relevant regulations may affect decision-making. Recognition of the complex set of considerations that should inform decision-making will guide gatekeepers in making justifiable choices regarding the use of limited and valuable resources.
Topics: Biomedical Research; Clinical Trials as Topic; Decision Making; Humans; Research Design; United States
PubMed: 26374683
DOI: 10.1177/1740774515597699 -
Journal of Alternative and... Mar 2019This scoping review evaluates two decades of methodological advances made by "whole systems research" (WSR) pioneers in the fields of traditional, complementary, and... (Review)
Review
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.
Topics: Biomedical Research; Clinical Trials as Topic; Complementary Therapies; Humans
PubMed: 30870019
DOI: 10.1089/acm.2018.0499 -
Contemporary Clinical Trials Feb 2023The GetReal Trial Tool is a decision support tool to assess the impact of design choices on generalizability of clinical trials to routine clinical practice, while...
BACKGROUND
The GetReal Trial Tool is a decision support tool to assess the impact of design choices on generalizability of clinical trials to routine clinical practice, while taking into account the risk of bias, precision, acceptability and operational feasibility. This study describes the validation of the GetReal Trial Tool.
METHODS
Twelve experts took part in the GetReal Trial tool validation using the protocols of 6 trials conducted with pragmatic elements. The tool entails 7 domains with a total of 43 questions. A pooled Kappa statistic (95% CI) using random effects model was estimated using Open Meta (analyst) software. The possible operational challenges were collated and discussed with the trialists that conducted the trials.
RESULTS
Agreement in the design choices made for the trial protocols was >50% for all the trials and all teams reached consensus during discussion. The pooled Kappa statistic (95% CI) was 0.236 (0.154-0.318). The GetReal Trial tool highlighted several operational challenges, of which almost half had been experienced previously by the trialists. Out of 25 additional operational challenges mentioned by the trialists, 76% were already highlighted by the tool. The tool was considered helpful to optimize trials right from the design stage.
CONCLUSION
The GetReal Trial Tool helps to scrutinize the choice of study design in the light of Real World Evidence generation. The tool identifies most of the operational challenges experienced by trialists to date. The tool serves the intended purpose of facilitating discussion and understanding more pragmatic design choices and their implications.
Topics: Humans; Research Design; Clinical Trials as Topic; Decision Support Techniques
PubMed: 36529438
DOI: 10.1016/j.cct.2022.107054 -
Clinical Trials (London, England) Feb 2022We need more pragmatic trials of interventions to improve care and outcomes for people living with Alzheimer's disease and related dementias. However, these trials...
BACKGROUND AND AIMS
We need more pragmatic trials of interventions to improve care and outcomes for people living with Alzheimer's disease and related dementias. However, these trials present unique methodological challenges in their design, analysis, and reporting-often, due to the presence of one or more sources of clustering. Failure to account for clustering in the design and analysis can lead to increased risks of Type I and Type II errors. We conducted a review to describe key methodological characteristics and obtain a "baseline assessment" of methodological quality of pragmatic trials in dementia research, with a view to developing new methods and practical guidance to support investigators and methodologists conducting pragmatic trials in this field.
METHODS
We used a published search filter in MEDLINE to identify trials more likely to be pragmatic and identified a subset that focused on people living with Alzheimer's disease or other dementias or included them as a defined subgroup. Pairs of reviewers extracted descriptive information and key methodological quality indicators from each trial.
RESULTS
We identified = 62 eligible primary trial reports published across 36 different journals. There were 15 (24%) individually randomized, 38 (61%) cluster randomized, and 9 (15%) individually randomized group treatment designs; 54 (87%) trials used repeated measures on the same individual and/or cluster over time and 17 (27%) had a multivariate primary outcome (e.g. due to measuring an outcome on both the patient and their caregiver). Of the 38 cluster randomized trials, 16 (42%) did not report sample size calculations accounting for the intracluster correlation and 13 (34%) did not account for intracluster correlation in the analysis. Of the 9 individually randomized group treatment trials, 6 (67%) did not report sample size calculations accounting for intracluster correlation and 8 (89%) did not account for it in the analysis. Of the 54 trials with repeated measurements, 45 (83%) did not report sample size calculations accounting for repeated measurements and 19 (35%) did not utilize at least some of the repeated measures in the analysis. No trials accounted for the multivariate nature of their primary outcomes in sample size calculation; only one did so in the analysis.
CONCLUSION
There is a need and opportunity to improve the design, analysis, and reporting of pragmatic trials in dementia research. Investigators should pay attention to the potential presence of one or more sources of clustering. While methods for longitudinal and cluster randomized trials are well developed, accessible resources and new methods for dealing with multiple sources of clustering are required. Involvement of a statistician with expertise in longitudinal and clustered designs is recommended.
Topics: Alzheimer Disease; Caregivers; Cluster Analysis; Humans; Pragmatic Clinical Trials as Topic; Randomized Controlled Trials as Topic; Research Design; Research Report
PubMed: 34841910
DOI: 10.1177/17407745211046672 -
Clinical Pharmacology and Therapeutics Jan 2022Concerns regarding both the limited generalizability and the slow pace of traditional randomized trials have led to calls for greater use of real-world evidence in the... (Review)
Review
Concerns regarding both the limited generalizability and the slow pace of traditional randomized trials have led to calls for greater use of real-world evidence in the evaluation of new treatments or products. Real-world clinical trials or pragmatic trials often differ from traditional clinical trials in the use of open-label or nonblinded treatments delivered by real-world clinicians in community practice settings. Blinding and standardization of treatment may sometimes be necessary for internal validity, but they may also obscure or distort meaningful differences between treatments. When investigators consider whether blinding of clinicians, patients, or assessors is necessary, we suggest they consider several specific questions: Will clinicians, patients, and assessors have expectations or preferences regarding benefits or adverse effects? How might those expectations affect treatment uptake, treatment adherence, or assessment of outcomes? Will expectations differ in the settings where trial results will be applied? How would blinding of treatment reduce biases? How would blinding obscure true differences between treatments? How would procedures necessary for blinding reduce acceptability or increase risk of trial participation? When investigators consider how strictly treatments should be standardized, we suggest they consider several specific questions: How would treatment effectiveness or safety vary according to clinician experience or expertise? What level of experience or expertise is available in potential trial settings and settings where trial results would be applied? Is some level of standardization necessary for valid inference? Considering any special vulnerabilities of the study population, is some level of standardization necessary to assure participant safety?
Topics: Double-Blind Method; Humans; Pragmatic Clinical Trials as Topic; Reference Standards; Research Design; Treatment Outcome
PubMed: 33829639
DOI: 10.1002/cpt.2256 -
Healthcare (Amsterdam, Netherlands) Mar 2019The National Institutes of Health (NIH) Health Care Systems (HCS) Research Collaboratory hosted a workshop to explore challenges and strategies for the dissemination,... (Review)
Review
Pragmatic clinical trials offer unique opportunities for disseminating, implementing, and sustaining evidence-based practices into clinical care: Proceedings of a workshop.
The National Institutes of Health (NIH) Health Care Systems (HCS) Research Collaboratory hosted a workshop to explore challenges and strategies for the dissemination, implementation, and sustainability of findings from pragmatic clinical trials (PCTs) embedded in HCS. PCTs are designed to assess the impact of interventions delivered in usual or real-world conditions and leverage existing infrastructure to answer important clinical questions. The goal of the workshop was to discuss strategies for conducting impactful future PCTs that bridge the gap between evidence, practice, and policy. This paper summarizes presentations about how to design and conduct PCTs embedded in HCS and use dissemination and implementation strategies during the planning and conduct of projects, emphasizing the ever-changing world of care delivery and the need for pragmatic trial operations to adapt at various levels of operation.
Topics: Education; Evidence-Based Practice; Humans; Information Dissemination; National Institutes of Health (U.S.); Pragmatic Clinical Trials as Topic; Program Evaluation; Research Design; United States
PubMed: 30594497
DOI: 10.1016/j.hjdsi.2018.12.003 -
BMC Health Services Research Nov 2022Transition from paediatric to adult heath care services is a challenging time for many adolescents with chronic illnesses and may include deterioration in illness...
Study protocol: a pragmatic trial reviewing the effectiveness of the TransitionMate mobile application in supporting self-management and transition to adult healthcare services for young people with chronic illnesses.
BACKGROUND
Transition from paediatric to adult heath care services is a challenging time for many adolescents with chronic illnesses and may include deterioration in illness control as a consequence of inadequate self-management skills, poor understanding of their chronic illness and failure to engage with adult services. Successful transfer of health care requires the development of self-management skills and increased autonomy. Mobile technology has been proposed as a modality to assist this process. Evidence is limited and generally restricted to illness specific applications. The TransitionMate app (TMApp) is a generic (non-illness specific) mobile application designed to support young people with chronic illness in their transition from paediatric to adult health care services. The overall aim of the study is to assess the effectiveness of TMApp in improving engagement and retention of adolescents with chronic illness within adult healthcare services, as well as preventing the deterioration in illness control and unplanned hospitalisations.
METHODS
The TransitionMate trial is a dual centre, pragmatic, single arm, mixed methods cohort study conducted within two university teaching tertiary paediatric hospitals in Australia. Data collection points are planned at 0, 6, 12 and 18 months. Outcome indicators include: usage of TransitionMate, engagement with adult services, quantitative markers of illness control, and unplanned hospital admissions. Data are collected through telephone interviews with the participants, their primary healthcare providers, electronic medical records and de-identified mobile application analytics. The development of the application involved co-design with recently transitioned young people with a number of chronic illnesses as well as online user experience in younger adolescents.
DISCUSSION
The TransitionMate study is the first identified trial of a generic mobile application designed to support adolescents with chronic illnesses during the transition process. Results are expected to provide novel insights into the value of technological tools in the transition space, especially their effectiveness in improving both the transition process and clinical outcomes of adolescents with chronic illnesses. Furthermore, the approach of a pragmatic study design may help identify research methods better designed to overcome inherent challenges in research involving adolescents, transition of care and use of mobile application technology.
TRIAL REGISTRATION
Registered retrospectively as of 30/1/2020 with Australian New Zealand Clinical Trials Registry: ACTRN12620000074998 .
Topics: Adolescent; Humans; Australia; Chronic Disease; Cohort Studies; Mobile Applications; Self-Management; Pragmatic Clinical Trials as Topic; Multicenter Studies as Topic; Transition to Adult Care
PubMed: 36447255
DOI: 10.1186/s12913-022-08536-8 -
BMJ Open Dec 2021Personal digital devices that provide health information, such as the Apple Watch, have developed an increasing array of cardiopulmonary tracking features which have...
INTRODUCTION
Personal digital devices that provide health information, such as the Apple Watch, have developed an increasing array of cardiopulmonary tracking features which have received regulatory clearance and are directly marketed to consumers. Despite their widespread and increasing use, data about the impact of personal digital device use on patient-reported outcomes and healthcare utilisation are sparse. Among a population of patients with atrial fibrillation and/or atrial flutter undergoing cardioversion, our primary aim is to determine the impact of the heart rate measurement, irregular rhythm notification, and ECG features of the Apple Watch on quality of life and healthcare utilisation.
METHODS AND ANALYSIS
We are conducting a prospective, open-label multicentre pragmatic randomised clinical trial, leveraging a unique patient-centred health data sharing platform for enrolment and follow-up. A total of 150 patients undergoing cardioversion for atrial fibrillation or atrial flutter will be randomised 1:1 to receive the Apple Watch Series 6 or Withings Move at the time of cardioversion. The primary outcome is the difference in the Atrial Fibrillation Effect on QualiTy-of-life global score at 6 months postcardioversion. Secondary outcomes include inpatient and outpatient healthcare utilisation. Additional secondary outcomes include a comparison of the Apple Watch ECG and pulse oximeter features with gold-standard data obtained in routine clinical care settings.
ETHICS AND DISSEMINATION
The Institutional Review Boards at Yale University, Mayo Clinic, and Duke University Health System have approved the trial protocol. This trial will provide important data to policymakers, clinicians and patients about the impact of the heart rate, irregular rhythm notification, and ECG features of widely used personal digital devices on patient quality of life and healthcare utilisation. Findings will be disseminated to study participants, at professional society meetings and in peer-reviewed journals.
TRIAL REGISTRATION NUMBER
NCT04468321.
Topics: Atrial Fibrillation; Atrial Flutter; Electric Countershock; Humans; Multicenter Studies as Topic; Pragmatic Clinical Trials as Topic; Prospective Studies; Quality of Life; Randomized Controlled Trials as Topic
PubMed: 35234659
DOI: 10.1136/bmjopen-2021-054550 -
BMJ Open Jan 2024It is encouraged to estimate the effectiveness of components within the enhanced recovery after surgery (ERAS) protocol through patient-reported outcomes, alongside...
Effectiveness of general anaesthesia with remimazolam tosilate on intraoperative haemodynamics and postoperative recovery: study protocol for a randomised, positive-controlled, pragmatic clinical trial (GARTH trial).
INTRODUCTION
It is encouraged to estimate the effectiveness of components within the enhanced recovery after surgery (ERAS) protocol through patient-reported outcomes, alongside doctor-reported outcomes and length of hospital stay. At present, studies on the contributions of optimal anaesthetic drugs within the ERAS protocol to patient-reported and doctor-reported outcomes are limited. Therefore, this study aims to pragmatically evaluate the effectiveness and safety of general anaesthesia (GA) with remimazolam tosilate within the ERAS protocol on intraoperative haemodynamics and postoperative recovery in adults undergoing elective surgeries, compared with propofol.
METHODS AND ANALYSIS
This study is a single-centre, randomised, blinded, positive-controlled, pragmatic clinical trial. A total of 900 patients, aged ≥18 years old, scheduled for an elective surgical procedure under GA will be included. Patients will be randomised in a 1:1 ratio to the remimazolam group (the GA with remimazolam tosilate within the ERAS protocol group) or propofol group (the GA with propofol within the ERAS protocol group), stratified by general surgery, thoracic surgery and other surgeries (including urological surgery and otolaryngology surgery). The primary outcomes include the 24-hour postoperative quality of recovery-40 score and the rate of intraoperative hypotension. Secondary endpoints include the rate of sedative hypotension requiring treatment, the haemodynamic profiles, the 72-hour postoperative quality of recovery-40 score, the functional anaesthetic capability, adverse events and complications, quality of life within 3 months as well as economic health outcomes.
ETHICS AND DISSEMINATION
This study protocol has been approved by the ethics committee of Guangdong Provincial People's Hospital (KY-H-2022-005-03-08). Dissemination plans will be presented at scientific meetings and in scientific publications.
TRIAL REGISTRATION NUMBER
ChiCTR2200062520.
Topics: Adolescent; Adult; Humans; Anesthesia, General; Anesthetics; Hemodynamics; Hypotension; Postoperative Complications; Propofol; Quality of Life; Randomized Controlled Trials as Topic; Pragmatic Clinical Trials as Topic
PubMed: 38176870
DOI: 10.1136/bmjopen-2023-073024