Pragmatic Clinical Research Research Articles

Understanding the role of induction, intensions and extensions in pragmatic clinical research and practice

BackgroundPragmatic clinical research methods are poorly understood, but essential to practice outcome-based medical or surgical care. Pragmatic research aims to verify the connections between medical knowledge and the reality of practice. Its methods can be understood by reviewing the problems of induction, as well as the related linguistic and mathematical notions of intensions and extensions. MethodsWe briefly review the source of problems with using inductive methods to gain knowledge, and the relationships between language, mathematics and reality. We discuss linguistic 'sense’ and ‘reference’, and the set-theory terms ‘intensions’ and ‘extensions’, which define the relationship between individuals and whichever pertinent collection these individuals comprise. Both concepts are essential to understand pragmatic medical research and evidence-based practice. ResultsPragmatic clinical research can be explained in terms of testing (in reality) the repeatability of various inductive referential and inferential steps used in clinical practice - from reliability, diagnostic accuracy, and prognostic studies to pragmatic trials. All pragmatic studies aim to verify the relationship between the extensions of the notions of symptoms, diagnoses, prognoses, treatments, and outcomes. The concepts of intensions and extensions also serve to understand ‘statistical significance’ in analyzing trial results, as well as problems related to eligibility criteria and subgroup analyses. The results of clinical studies can be generalized to the extent that they have been tested in numerous and widely different individuals. ConclusionThe notions of sense and reference, and of intensions and extensions, help explain the role pragmatic clinical research methods can play in optimizing care.

The interplay between the microbiota and opioid in the treatment of neuropathic pain.

Neuropathic pain (NP) is characterized by its complex and multifactorial nature and limited responses to opioid therapy; NP is associated with risks of drug resistance, addiction, difficulty in treatment cessation, and psychological disorders. Emerging research on gut microbiota and their metabolites has demonstrated their effectiveness in alleviating NP and augmenting opioid-based pain management, concurrently mitigating the adverse effects of opioids. This review addresses the following key points: (1) the current advances in gut microbiota research and the challenges in using opioids to treat NP, (2) the reciprocal effects and benefits of gut microbiota on NP, and (3) the interaction between opioids with gut microbiota, as well as the benefits of gut microbiota in opioid-based treatment of NP. Through various intricate mechanisms, gut microbiota influences the onset and progression of NP, ultimately enhancing the efficacy of opioids in the management of NP. These insights pave the way for further pragmatic clinical research, ultimately enhancing the efficacy of opioid-based pain management.

Why Should the FDA Focus on Pragmatic Clinical Research?

This Viewpoint from the FDA discusses how pragmatic clinical research—assessment that uses real-world data, often in combination with research data, after initial marketing approval—can help in evaluation of new technologies, benefit research sites in underresourced settings, and better inform regulatory decisions and clinical practice.

Challenges in IBD Research 2024: Pragmatic Clinical Research.

Pragmatic clinical research is 1 of the 5 focus areas of the Challenges in IBD Research 2024, a multidisciplinary effort by scientists, clinicians, patients, and funders to identify priorities for patient-centric research. This summary provides a comprehensive overview of current gaps in inflammatory bowel disease (IBD) clinical research and actionable approaches to address them. This review is focused on identifying research that is needed to achieve the best outcomes for patients in clinical practice. Research gaps include understanding the needs of understudied patient groups and addressing barriers to care so all patients receive optimal care, validating and using biomarkers to enable early diagnosis and result in better outcomes for adults and children with IBD, and determining the optimal sequencing of treatments (medical, surgical, adjunct) in children and adults. Inclusive pragmatic research is needed to address these gaps and lead to improvements in patient care and outcomes for all populations of patients with IBD.

Challenges in IBD Research 2024: Precision Medicine.

Precision medicine is part of 5 focus areas of the Challenges in IBD Research 2024 research document, which also includes preclinical human IBD mechanisms, environmental triggers, novel technologies, and pragmatic clinical research. Building on Challenges in IBD Research 2019, the current Challenges aims to provide a comprehensive overview of current gaps in inflammatory bowel diseases (IBDs) research and deliver actionable approaches to address them with a focus on how these gaps can lead to advancements in interception, remission, and restoration for these diseases. The document is the result of multidisciplinary input from scientists, clinicians, patients, and funders, and represents a valuable resource for patient-centric research prioritization. In particular, the precision medicine section is focused on the main research gaps in elucidating how to bring the best care to the individual patient in IBD. Research gaps were identified in biomarker discovery and validation for predicting disease progression and choosing the most appropriate treatment for each patient. Other gaps were identified in making the best use of existing patient biosamples and clinical data, developing new technologies to analyze large datasets, and overcoming regulatory and payer hurdles to enable clinical use of biomarkers. To address these gaps, the Workgroup suggests focusing on thoroughly validating existing candidate biomarkers, using best-in-class data generation and analysis tools, and establishing cross-disciplinary teams to tackle regulatory hurdles as early as possible. Altogether, the precision medicine group recognizes the importance of bringing basic scientific biomarker discovery and translating it into the clinic to help improve the lives of IBD patients.

Overview to Challenges in IBD 2024-2029.

The mission of the Crohn's & Colitis Foundation is to cure Crohn's disease and ulcerative colitis and to improve the quality of lives of patients living with these diseases-in other words, to care and cure. To achieve these missions, there is a need to identify and prioritize research gaps and approaches to address these gaps, which is the aim of Challenges in IBD 2024. The Foundation convened close to 80 experts in inflammatory bowel disease (IBD), including researchers, clinicians, patients and caregivers, funders, industry representatives, and Foundation scientific staff and organized them into 5 workgroups, one for each of the 5 Challenges topics: Preclinical Human IBD Mechanisms, Environmental Triggers, Precision Medicine, Novel Technologies, and Pragmatic Clinical Research. The findings of these groups outline a research agenda that intends to change the research paradigm in IBD by introducing 2 concepts in the course of IBD that warrant specific focus: interception (during the preclinical phase) and restoration of normal physiology after remission is achieved. We hope these reviews will stimulate innovations in our understanding and management of IBD.

Challenges in IBD Research 2024: Preclinical Human IBD Mechanisms.

Preclinical human inflammatory bowel disease (IBD) mechanisms is one of 5 focus areas of the Challenges in IBD Research 2024 document, which also includes environmental triggers, novel technologies, precision medicine, and pragmatic clinical research. Herein, we provide a comprehensive overview of current gaps in inflammatory bowel diseases research that relate to preclinical research and deliver actionable approaches to address them with a focus on how these gaps can lead to advancements in IBD interception, remission, and restoration. The document is the result of multidisciplinary input from scientists, clinicians, patients, and funders and represents a valuable resource for patient-centric research prioritization. This preclinical human IBD mechanisms section identifies major research gaps whose investigation will elucidate pathways and mechanisms that can be targeted to address unmet medical needs in IBD. Research gaps were identified in the following areas: genetics, risk alleles, and epigenetics; the microbiome; cell states and interactions; barrier function; IBD complications (specifically fibrosis and stricturing); and extraintestinal manifestations. To address these gaps, we share specific opportunities for investigation for basic and translational scientists and identify priority actions.

Using Measurement-Based Care as a Precision Medicine Strategy for Substance Use Disorders.

Precision medicine prioritizes characterization of individual patient parameters to optimize care and this review evaluates measurement-based care (MBC) as a strategy for doing so in the treatment of substance use disorders (SUD). Measurement-based care refers to the systematic use of validated assessments to inform diagnosis and treatment planning, with varying frequency of assessments. Despite the seemingly obvious grounds for the use of MBC in treating SUD, systematic implementation to date has been limited. Thus, the goal of this review is to evaluate efforts to date and to stimulate greater consideration of MBC models in addictions programs. Data from two published randomized controlled trials and findings from pragmatic clinical research highlight the potential utility of MBC in the SUD treatment settings. Despite these findings, the existing literature indicates the high need for larger-scale clinical trials and quality improvement programs. Potential barriers to the implementation of MBC for SUD are outlined at the patient, provider, organization, and system levels, as well as the challenges associated with the use of MBC programs for clinical research. Critical thinking considerations and risk mitigation strategies are offered toward advancing MBC for SUD beyond the current nascent state. Collectively, the existing data confirm that MBC is a suitable and promising strategy for applying a precision medicine approach in SUD treatment, warranting further implementation efforts and scientific inquiry.

Digital behavioural signatures reveal trans-diagnostic clusters of Schizophrenia and Alzheimer's disease patients

The current neuropsychiatric nosological categories underlie pragmatic treatment choice, regulation and clinical research but does not encompass biological rationale. However, subgroups of patients suffering from schizophrenia or Alzheimer's disease have more in common than the neuropsychiatric nature of their condition, such as the expression of social dysfunction. The PRISM project presents here initial quantitative biological insights allowing the first steps toward a novel trans-diagnostic classification of psychiatric and neurological symptomatology intended to reinvigorate drug discovery in this area. In this study, we applied spectral clustering on digital behavioural endpoints derived from passive smartphone monitoring data in a subgroup of Schizophrenia and Alzheimer's disease patients, as well as age matched healthy controls, as part of the PRISM clinical study. This analysis provided an objective social functioning characterization with three differential clusters that transcended initial diagnostic classification and was shown to be linked to quantitative neurobiological parameters assessed. This emerging quantitative framework will both offer new ways to classify individuals in biologically homogenous clusters irrespective of their initial diagnosis, and also offer insights into the pathophysiological mechanisms underlying these clusters.

Integrating pragmatic and implementation science randomized clinical trial approaches: a PRagmatic Explanatory Continuum Indicator Summary-2 (PRECIS-2) analysis

BackgroundOver the past two decades, pragmatic and implementation science clinical trial research methods have advanced substantially. Pragmatic and implementation studies have natural areas of overlap, particularly relating to the goal of using clinical trial data to leverage health care system policy changes. Few investigations have addressed pragmatic and implementation science randomized trial methods development while also considering policy impact.MethodsThe investigation used the PRagmatic Explanatory Continuum Indicator Summary-2 (PRECIS-2) and PRECIS-2-Provider Strategies (PRECIS-2-PS) tools to evaluate the design of two multisite randomized clinical trials that targeted patient-level effectiveness outcomes, provider-level practice changes and health care system policy. Seven raters received PRECIS-2 training and applied the tools in the coding of the two trials. Descriptive statistics were produced for both trials, and PRECIS-2 wheel diagrams were constructed. Interrater agreement was assessed with the Intraclass Correlation (ICC) and Kappa statistics. The Rapid Assessment Procedure Informed Clinical Ethnography (RAPICE) qualitative approach was applied to understanding integrative themes derived from the PRECIS-2 ratings and an end-of-study policy summit.ResultsThe ICCs for the composite ratings across the patient and provider-focused PRECIS-2 domains ranged from 0.77 to 0.87, and the Kappa values ranged from 0.25 to 0.37, reflecting overall fair-to-good interrater agreement for both trials. All four PRECIS-2 wheels were rated more pragmatic than explanatory, with composite mean and median scores ≥ 4. Across trials, the primary intent-to-treat analysis domain was consistently rated most pragmatic (mean = 5.0, SD = 0), while the follow-up/data collection domain was rated most explanatory (mean range = 3.14–3.43, SD range = 0.49–0.69). RAPICE field notes identified themes related to potential PRECIS-2 training improvements, as well as policy themes related to using trial data to inform US trauma care system practice change; the policy themes were not captured by the PRECIS-2 ratings.ConclusionsThe investigation documents that the PRECIS-2 and PRECIS-2-PS can be simultaneously used to feasibly and reliably characterize clinical trials with patient and provider-level targets. The integration of pragmatic and implementation science clinical trial research methods can be furthered by using common metrics such as the PRECIS-2 and PRECIS-2-PS. Future study could focus on clinical trial policy research methods development.Trial registrationDO-SBIS ClinicalTrials.gov NCT00607620. registered on January 29, 2008. TSOS ClinicalTrials.gov NCT02655354, registered on July 27, 2015.

Measurement-Based Care in Treatment of Substance Use Disorders

IntroductionMeasurement-Based Care (MBC) is an emerging healthcare model with a number of potential advantages over traditional approaches for the treatment of substance use disorder (SUD). Despite SUD treatment programs being theoretically well suited for the implementation of MBC, its uptake has been minimal, which in turn limits further research, knowledge synthesis, and translation into clinical practice.ObjectivesThe goal of this knowledge synthesis project is to stimulate greater consideration of MBC models in addictions programs, with three interrelated objectives: 1. To summarize the existing evidence from research literature 2. To complement the literature findings with the data from our clinical research and quality improvement projects 3. To explore potential risks and difficulties of MBC implementation in the SUD treatment programsMethodsNarrative review. Knowledge synthesis.ResultsTo date, only two published randomized controlled trials, which along with the data from our pragmatic clinical research, support the wider implementation of MBC in the substance abuse treatment settings, but also indicate the high need for larger-scale clinical trials and quality improvement programs. Potential barriers to the implementation of MBC for SUD are outlined at the patient, provider, organization, and system levels, as well as challenges associated with the use of MBC programs for clinical research. Critical thinking considerations and risk mitigation strategies are offered toward advancing MBC for SUD beyond the current nascent state.ConclusionsThe state-of-the-art of MBC in SUD care settings reviewed and the strategies for further development from adminsitrative, clinical, and research prospectives outlined.DisclosureNo significant relationships.

The Management of Distal Clavicle Fractures - A Survey of UK Shoulder and Elbow Surgeons.

BackgroundDistal clavicle fractures (DCF) are a management challenge frequently encountered by shoulder surgeons. Despite an array of surgical fixation strategies, the indications and role of surgery are unclear, with there being no gold standard or consensus regarding their management. The aim of this study was to identify current United Kingdom (UK) clinical practices relating to DCFs and to inform a future randomised control trial (RCT).MethodsAn online survey was sent to the consultant surgeon members of the British Elbow and Shoulder Society (BESS). Questions covered respondent indications for surgical fixation, important factors considered for management of DCFs, fixation strategies, the volume of patients treated, and willingness to participate in the conduct of a randomized trial.ResultsThe response rate was 84/327 (26%). 64-67% of respondents reported surgically managing DCFs classified as Neer type 2A, 2B and 5. The most important factors considered by surgeons when deciding between operative and nonoperative intervention were degree of displacement (90%), clinical assessment of impending open fracture (87%), and age of the patient (74%). For conservatively managed DCFs, the preferred length of complete immobilization was 2-4 weeks (46%), followed by 4-8 weeks (17%). 30% reported not immobilizing their patients at all. For operative intervention, the locking plate was the preferred fixation method by most respondents (68%), although there was no clear consensus regarding other fixation methods. Most surgeons (52%) reported treating a low volume of patients with DCFs (0-10) per year. 58% of respondents were willing to randomize patients to non-operative treatment in a multi-centre RCT, with a further 22% undecided. Finally, 68% (n=79) of respondents would consider being co-investigators in such a trial.ConclusionThere is considerable heterogeneity in the management of patients with DCFs in the UK. The indications for surgery and the optimal surgical fixation method remain uncertain. There is a clear need for pragmatic multi-centre clinical research in this area.

Group-Based Exercise in CKD Stage 3b to 4: A Randomized Clinical Trial

Rationale & ObjectiveWe aimed to test interventions to improve physical activity in persons with advanced chronic kidney disease not yet receiving dialysis.Study DesignRandomized controlled trial with parallel-group design.Setting & ParticipantsWe embedded a pragmatic referral to exercise programming in high-volume kidney clinics servicing diverse populations in San Jose, CA, and Atlanta, GA. We recruited 56 participants with estimated glomerular filtration rates < 45 mL/min/1.73 m2.InterventionsWe randomly assigned participants to a mobile health (mHealth) group—wearable activity trackers and fitness professional counseling, or an Exercise is Medicine intervention framework (EIM) group—mHealth components plus twice-weekly small-group directed exercise sessions customized to persons with kidney disease. We performed assessments at baseline, 8 weeks at the end of active intervention, and 16 weeks after passive follow-up and used multilevel mixed models to assess between-group differences.OutcomesActivity tracker total daily step count.ResultsOf 56 participants, 86% belonged to a racial/ethnic minority group; randomly assigned groups were well balanced on baseline step count. In intention-to-treat analyses, the EIM and mHealth groups both experienced declines in daily step counts, but there was an attenuated reduction in light intensity physical activity (standard error 0.2 [5.8] vs −8.5 [5.4] min/d; P = 0.08) in the EIM compared with the mHealth group at 8 weeks. In as-treated analyses, total daily step count, distance covered, and light and moderate-vigorous activity minutes per day improved in the EIM group and declined in the mHealth group at 8 weeks (standard error +335 [506] vs −884 [340] steps per day; P = 0.05; P < 0.05 for secondary measures), but group differences faded at 16 weeks. There were no differences in quality-of-life and mental health measures during the study.LimitationsSmall sample size, limited duration of study, assessment of intermediate outcomes (steps per day).ConclusionsA clinic-integrated referral to small-group exercise sessions is feasible, safe, and moderately effective in improving physical activity in an underserved population with high comorbid conditions.FundingNormon S Coplon Applied Pragmatic Clinical Research program.Trial RegistrationNCT03311763

Pediatric Trials Network: Stakeholder views on thanking families and providing study findings on pragmatic pediatric clinical research

We conducted formative research using in-depth interviews to identify preferences for and anticipated responses to receiving thank you notes and lay summaries of aggregate results among caregivers and adolescent participants of pragmatic pediatric studies conducted by the National Institute of Health-sponsored Pediatric Trials Network. We analyzed the data using qualitative thematic analysis. Nearly all participants said receiving a thank you note would make them feel valued, appreciated, and proud because they contributed to science. Similarly, nearly all participants said that receiving a lay summary of research results would make them aware of their role in improving the lives of children, feel like they are an active partner in research, and believe that researchers want to keep them informed. Participants also said that receiving a thank you note or lay summary may motivate them to participate in future research. Providing thank you notes as part of study participation should become a standard clinical trial practice, similar to the practice of providing lay summaries.

PCORnet® 2020: current state, accomplishments, and future directions

ObjectiveTo describe PCORnet, a clinical research network developed for patient-centered outcomes research on a national scale. Study Design and SettingDescriptive study of the current state and future directions for PCORnet. We conducted cross-sectional analyses of the health systems and patient populations of the 9 Clinical Research Networks and 2 Health Plan Research Networks that are part of PCORnet. ResultsWithin the Clinical Research Networks, electronic health data are currently collected from 337 hospitals, 169,695 physicians, 3,564 primary care practices, 338 emergency departments, and 1,024 community clinics. Patients can be recruited for prospective studies from any of these clinical sites. The Clinical Research Networks have accumulated data from 80 million patients with at least one visit from 2009 to 2018. The PCORnet Health Plan Research Network population of individuals with a valid enrollment segment from 2009 to 2019 exceeds 60 million individuals, who on average have 2.63 years of follow-up. ConclusionPCORnet’s infrastructure comprises clinical data from a diverse cohort of patients and has the capacity to rapidly access these patient populations for pragmatic clinical trials, epidemiological research, and patient-centered research on rare diseases.

Mixed-effects models for the design and analysis of stepped wedge cluster randomized trials: An overview.

The stepped wedge cluster randomized design has received increasing attention in pragmatic clinical trials and implementation science research. The key feature of the design is the unidirectional crossover of clusters from the control to intervention conditions on a staggered schedule, which induces confounding of the intervention effect by time. The stepped wedge design first appeared in the Gambia hepatitis study in the 1980s. However, the statistical model used for the design and analysis was not formally introduced until 2007 in an article by Hussey and Hughes. Since then, a variety of mixed-effects model extensions have been proposed for the design and analysis of these trials. In this article, we explore these extensions under a unified perspective. We provide a general model representation and regard various model extensions as alternative ways to characterize the secular trend, intervention effect, as well as sources of heterogeneity. We review the key model ingredients and clarify their implications for the design and analysis. The article serves as an entry point to the evolving statistical literatures on stepped wedge designs.

Pragmatic clinical trials: Increasing the rate of translating nursing research into practice†.

Nursing research worldwide is committed to rigorous scientific inquiry that provides a significant body of knowledge to advance nursing practice. One way to advance nursing practice is to increase the rate at which nursing research findings are translated into clinical practice, and one way to do that is to use pragmatic clinical trial research designs. This article aims to describe and advocate for the increased use of pragmatic clinical trials in nursing research and to provide a summary of one nursing pragmatic clinical trial. A review and discussion of the features of pragmatic clinical trials. This article describes the principles and benefits of pragmatic clinical trials. Nurse researchers who use these principles will generate results that are more actionable, patient-centered, and relevant in clinical practice. Focusing on research that provides practical evidence that can be translated into evidence-based practice is an important way to improve the environment for nursing research that leads more rapidly to improved nursing practice. Embracing and increasing our use of pragmatic clinical trial design concepts in nursing research can enhance the significance of our findings and facilitate the translation of our research into practice.

Overcoming barriers to the use of metformin: patient and provider perspectives.

BackgroundMetformin is the first-line treatment for type 2 diabetes mellitus. Observational studies show lower rates of use than would be expected from clinical guidelines.ObjectiveWe undertook a qualitative study of barriers to metformin use from the patient and provider perspective.DesignPatient focus group, patient individual interviews, provider interviews, and chart review. Purposive sampling of patients and providers in New York State.ParticipantsSeven one-on-one patient interviews, one focus group with 13 patients, 10 provider interviews, and manual review of 1259 charts.ApproachGrounded theory.ResultsBoth providers and patients cited potential health benefits as strong reasons to take metformin and describe it as the first-line drug for diabetes. Patients and providers both cited gastrointestinal side effects as the primary barrier to metformin use. Patients described adapting to these side effects and taking metformin at a time that minimizes them. In contrast, providers emphasized dose titration and the use of extended-release formulation as tools for minimizing side effects but were uncertain about the effectiveness of these strategies.ConclusionMetformin is positively viewed by patients and providers, but gastrointestinal side effects are a barrier to its use. There is some consensus on basic measures to improve its tolerability, but these measures are not consistently applied and lack evidence establishing their effectiveness. Pragmatic clinical trial research on optimal dose, formulation, and counseling for new metformin users should be considered.

Public views regarding the responsibility of patients, clinicians, and institutions to participate in research in the United States.

The need for more and better evidence to inform clinical decision making among all stakeholders has fueled calls for creating learning healthcare systems. The successful realization of a learning healthcare system seems to assume that various parties have a responsibility to participate in learning activities, including research. The objective of this study was to determine whether members of the general public perceive an ethical responsibility to participate in pragmatic clinical research that would be inherent to a learning health system. A total of 2994 English-speaking adults completed a nationally representative online survey. About two-thirds of respondents were relatively neutral regarding a responsibility for themselves and others to participate in research; the remainder felt that they and others did not have a responsibility to participate in research. Efforts to justify and develop a robust learning health system in an ethically acceptable fashion need to take these findings into account.

Challenges in IBD Research: Pragmatic Clinical Research.

Pragmatic clinical research is part of five focus areas of the Challenges in IBD research document, which also includes preclinical human IBD mechanisms, environmental triggers, novel technologies, and precision medicine. The Challenges in IBD research document provides a comprehensive overview of current gaps in inflammatory bowel diseases (IBD) research and delivers actionable approaches to address them. It is the result of multidisciplinary input from scientists, clinicians, patients, and funders, and represents a valuable resource for patient centric research prioritization. In particular, the pragmatic clinical research section is focused on highlighting gaps that need to be addressed in order to optimize and standardize IBD care. Identified gaps include: 1) understanding the incidence and prevalence of IBD; 2) evaluating medication positioning to increase therapeutic effectiveness; 3) understanding the utility of therapeutic drug monitoring (TDM); 4) studying pain management; and 5) understanding healthcare economics and resources utilization. To address these gaps, there is a need to emphasize the use of emerging data sources and real-world evidence to better understand epidemiologic and therapeutic trends in IBD, expanding on existing data to better understand how and where we should improve care. Proposed approaches include epidemiological studies in ethnically and geographically diverse cohorts to estimate incidence and prevalence of IBD and impact of diversity on treatment patterns and outcomes. The implementation of new clinical trial design and methodologies will be essential to evaluate optimal medication positioning, appropriate use of TDM in adults and children, and multidisciplinary approaches to IBD pain management and its impact on healthcare resources.