Principles and procedures for data and safety monitoring in pragmatic clinical trials

Abstract Background All clinical trial investigators have ethical and regulatory obligations to monitor participant safety and trial integrity. Specific procedures for meeting these obligations, however, may differ substantially between pragmatic trials and traditional explanatory clinical trials. Methods/Results Appropriate monitoring of clinical trials typically includes assessing rate of recruitment or enrollment; monitoring safe and effective delivery of study treatments; assuring that study staff act to minimize risks; monitoring quality and timeliness of study data; and considering interim analyses for early detection of benefit, harm, or futility. Each of these responsibilities applies to pragmatic clinical trials. Just as design of pragmatic trials typically involves specific and necessary departures from methods of explanatory clinical trials, appropriate monitoring of pragmatic trials typically requires specific departures from monitoring procedures used in explanatory clinical trials. We discuss how specific aspects of pragmatic trial design and operations influence selection of monitoring procedures and illustrate those choices using examples from three ongoing pragmatic trials conducted by the Mental Health Research Network. Conclusions Pragmatic trial investigators should not routinely adopt monitoring procedures used in explanatory clinical trials. Instead, investigators should consider core principles of trial monitoring and design monitoring procedures appropriate for each pragmatic trial.

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INTEREST GROUP SESSION—ALZHEIMER'S DISEASE AND RELATED DIMENTIAS: OPPORTUNITIES AND CHALLENGES TO DEVELOPING AND TESTING PRAGMATIC ADRD INTERVENTIONS

Innovation in Aging ◽

10.1093/geroni/igz038.1324 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

pp. S363-S363

Author(s):

Abraham A Brody ◽

Laura N Gitlin

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trials ◽

Real World ◽

Psychological Symptoms ◽

Wide Spectrum ◽

Pragmatic Trial ◽

Intervention Development ◽

Pragmatic Trials ◽

Pragmatic Clinical Trials

Abstract Many clinical trials have been performed to develop the evidence for caring for persons with Alzheimer’s Disease and Related Disorders (ADRD) in tightly controlled settings. These trials have found efficacy of a wide spectrum of interventions to address issues from advanced care planning to behavioral and psychological symptoms of dementia (BPSD). However, few ADRD interventions have been tested in wide-scale pragmatic fashion in long term supportive settings (LTSS) such as nursing homes, primary care clinics, hospices, or community based organizations. This is due to a variety factors, principle amongst them are the difficulty in implementing pragmatic trials, and that many of the interventions developed in tightly controlled settings are not directly translatable to real-world settings. Without translating and testing interventions in real world settings, the evidence base remains largely inaccessible to the end user, the persons with ADRD and their caregivers. Moreover, effectiveness remains unclear. The lack of pragmatic trials in ADRD exists despite significant recent investment from the NIH Office of the Director in a health systems collaboratory to support pragmatic clinical trials. In 2018, NIA therefore released a call for 2-phase intervention development and pragmatic trial testing via an R61-R33 mechanism (PAR-18-585). Four proposals were funded in September 2018 from this PAR. This symposium will explore the opportunities and challenges present in developing and testing pragmatic interventions in ADRD in LTSS. The speakers will also share specific scientific methodological and implementation questions that need to be addressed in applying for pragmatic trial awards.

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Optimizing the Impact of Pragmatic Clinical Trials for Veteran and Military Populations: Lessons From the Pain Management Collaboratory

Military Medicine ◽

10.1093/milmed/usab458 ◽

2021 ◽

Author(s):

Joseph Ali ◽

Margaret Antonelli ◽

Lori Bastian ◽

William Becker ◽

Cynthia A Brandt ◽

...

Keyword(s):

Clinical Trials ◽

Pain Management ◽

Pragmatic Trial ◽

Dissemination And Implementation ◽

Large Network ◽

Military Health ◽

Healthcare Needs ◽

Unmet Healthcare Needs ◽

Pragmatic Clinical Trials ◽

The Impact

ABSTRACT Pragmatic clinical trials (PCTs) are well-suited to address unmet healthcare needs, such as those arising from the dual public health crises of chronic pain and opioid misuse, recently exacerbated by the COVID-19 pandemic. These overlapping epidemics have complex, multifactorial etiologies, and PCTs can be used to investigate the effectiveness of integrated therapies that are currently available but underused. Yet individual pragmatic studies can be limited in their reach because of existing structural and cultural barriers to dissemination and implementation. The National Institutes of Health, Department of Defense, and Department of Veterans Affairs formed an interagency research partnership, the Pain Management Collaboratory. The partnership combines pragmatic trial design with collaborative tools and relationship building within a large network to advance the science and impact of nonpharmacological approaches and integrated models of care for the management of pain and common co-occurring conditions. The Pain Management Collaboratory team supports 11 large-scale, multisite PCTs in veteran and military health systems with a focus on team science with the shared aim that the “whole is greater than the sum of the parts.” Herein, we describe this integrated approach and lessons learned, including incentivizing all parties; proactively offering frequent opportunities for problem-solving; engaging stakeholders during all stages of research; and navigating competing research priorities. We also articulate several specific strategies and their practical implications for advancing pain management in active clinical, “real-world,” settings.

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Poor implementation of the EU clinical trial regulation is a major threat for pragmatic trials in European countries

Epidemiology and Psychiatric Sciences ◽

10.1017/s2045796020000396 ◽

2020 ◽

Vol 29 ◽

Author(s):

Giovanni Ostuzzi ◽

Chiara Gastaldon ◽

Carlo Petrini ◽

Brian Godman ◽

Corrado Barbui

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

European Countries ◽

Pragmatic Trials ◽

Research And Practice ◽

Major Threat ◽

Pragmatic Clinical Trials ◽

Clinical Trial Regulation ◽

The Eu

Abstract The principle of pragmatism in clinical trials has been broadly recognised as a way to close the gap between research and practice. In this contribution, we argue that the conduct of pragmatic clinical trials in Europe may be hampered by poor implementation of current European Union's Clinical Trial Regulation No. 536/2014.

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Design and implementation of pragmatic clinical trials using the electronic medical record and an adaptive design

JAMIA Open ◽

10.1093/jamiaopen/ooy017 ◽

2018 ◽

Vol 1 (1) ◽

pp. 99-106 ◽

Cited By ~ 6

Author(s):

Kelly Claire Simon ◽

Samuel Tideman ◽

Laura Hillman ◽

Rebekah Lai ◽

Raman Jathar ◽

...

Keyword(s):

Clinical Trials ◽

Medical Record ◽

Electronic Medical Record ◽

Adaptive Design ◽

Point Of Care ◽

Phase 1 ◽

Clinical Practices ◽

Pragmatic Trials ◽

Clinical Workflow ◽

Pragmatic Clinical Trials

AbstractObjectivesTo demonstrate the feasibility of pragmatic clinical trials comparing the effectiveness of treatments using the electronic medical record (EMR) and an adaptive assignment design.MethodsWe have designed and are implementing pragmatic trials at the point-of-care using custom-designed structured clinical documentation support and clinical decision support tools within our physician’s typical EMR workflow. We are applying a subgroup based adaptive design (SUBA) that enriches treatment assignments based on baseline characteristics and prior outcomes. SUBA uses information from a randomization phase (phase 1, equal randomization, 120 patients), to adaptively assign treatments to the remaining participants (at least 300 additional patients total) based on a Bayesian hierarchical model. Enrollment in phase 1 is underway in our neurology clinical practices for 2 separate trials using this method, for migraine and mild cognitive impairment (MCI).ResultsWe are successfully collecting structured data, in the context of the providers’ clinical workflow, necessary to conduct our trials. We are currently enrolling patients in 2 point-of-care trials of non-inferior treatments. As of March 1, 2018, we have enrolled 36% of eligible patients into our migraine study and 63% of eligible patients into our MCI study. Enrollment is ongoing and validation of outcomes has begun.DiscussionThis proof of concept article demonstrates the feasibility of conducting pragmatic trials using the EMR and an adaptive design.ConclusionThe demonstration of successful pragmatic clinical trials based on a customized EMR and adaptive design is an important next step in achieving personalized medicine and provides a framework for future studies of comparative effectiveness.

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Children’s Oncology Group (COG) clinical trials as exemplars of pragmatism in clinical research.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e18188 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e18188-e18188

Author(s):

Nupur Mittal ◽

Anil George ◽

Lizette Leanos ◽

Paul Kent

Keyword(s):

Clinical Trials ◽

Clinical Research ◽

Pragmatic Trial ◽

Standard Of Care ◽

The United States ◽

Phase Iii ◽

President Obama ◽

Explanatory Trial ◽

Phase Iii Clinical Trials ◽

Pragmatic Clinical Trials

e18188 Background: In 2016, President Obama announced the “Moonshot Cancer Initiative” to advance cancer research. One of the key components of this initiative is promoting enrollment in pragmatic clinical trials and data sharing. As described in 2009 by Thorpe et al, using the 9-domian PRECIS-2 tool, a ‘pragmatic’ trial, as opposed to an ‘explanatory’ trial used to confirm a physiologic hypothesis, is one in which the intervention can be immediately applied into real-world clinical practice (J of Clin Epi:2009). In the US, 60%-90% children are enrolled on COG research trials. State-of-the-art treatment for a child is derived from superior therapy identified in prior trials which then serves as the standard arm of subsequent phase-III trials and becomes the de facto practice guideline and ‘standard of care’ .To accomplish this goal, COG shares its data among the 242 member institutions.Our objective is to assess “pragmatism” in COG trials. Methods: We analyzed the 158 COG phase III clinical trials between 2006-2016 for all 9 domains of the PRECIS-2 (Table 1) and graded them from 1-5 (most explanatory to most pragmatic). Results: Out of 152 phase III clinical trials on the COG website, 138 (91%) scored 5/5 for all 9 PRECIS pragmatic domains and 148 (98%) scored >4. The scoring for all 9 domains is in table 1. Conclusions: COG provides nearly all children in the United States access to pragmatic phase III research as outlined in the Moonshot Goals. Goal of merging evidence-based standard care accessible to all and conducting well- designed clinical research to identify the best therapies has been accomplished by COG and should serve as an example to other cancer organizations. 9 domains of PRECIS-2 to assess pragmatism in clinical trials. [Table: see text]

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Computable Phenotype Implementation for a National, Multicenter Pragmatic Clinical Trial

Circulation Cardiovascular Quality and Outcomes ◽

10.1161/circoutcomes.119.006292 ◽

2020 ◽

Vol 13 (6) ◽

Cited By ~ 1

Author(s):

Faraz S. Ahmad ◽

Iben M. Ricket ◽

Bradley G. Hammill ◽

Lisa Eskenazi ◽

Holly R. Robertson ◽

...

Keyword(s):

Cardiovascular Disease ◽

Clinical Trial ◽

Clinical Trials ◽

Large Scale ◽

Research Network ◽

Administrative Claims ◽

Atherosclerotic Cardiovascular Disease ◽

Research Networks ◽

Pragmatic Clinical Trial ◽

Pragmatic Clinical Trials

Background: Many large-scale cardiovascular clinical trials are plagued with escalating costs and low enrollment. Implementing a computable phenotype, which is a set of executable algorithms, to identify a group of clinical characteristics derivable from electronic health records or administrative claims records, is essential to successful recruitment in large-scale pragmatic clinical trials. This methods paper provides an overview of the development and implementation of a computable phenotype in ADAPTABLE (Aspirin Dosing: a Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness)—a pragmatic, randomized, open-label clinical trial testing the optimal dose of aspirin for secondary prevention of atherosclerotic cardiovascular disease events. Methods and Results: A multidisciplinary team developed and tested the computable phenotype to identify adults ≥18 years of age with a history of atherosclerotic cardiovascular disease without safety concerns around using aspirin and meeting trial eligibility criteria. Using the computable phenotype, investigators identified over 650 000 potentially eligible patients from the 40 participating sites from Patient-Centered Outcomes Research Network—a network of Clinical Data Research Networks, Patient-Powered Research Networks, and Health Plan Research Networks. Leveraging diverse recruitment methods, sites enrolled 15 076 participants from April 2016 to June 2019. During the process of developing and implementing the ADAPTABLE computable phenotype, several key lessons were learned. The accuracy and utility of a computable phenotype are dependent on the quality of the source data, which can be variable even with a common data model. Local validation and modification were required based on site factors, such as recruitment strategies, data quality, and local coding patterns. Sustained collaboration among a diverse team of researchers is needed during computable phenotype development and implementation. Conclusions: The ADAPTABLE computable phenotype served as an efficient method to recruit patients in a multisite pragmatic clinical trial. This process of development and implementation will be informative for future large-scale, pragmatic clinical trials. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02697916.

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Stakeholder Engagement in Pragmatic Clinical Trials: Emphasizing Relationships to Improve Pain Management Delivery and Outcomes

Pain Medicine ◽

10.1093/pm/pnaa333 ◽

2020 ◽

Vol 21 (Supplement_2) ◽

pp. S13-S20

Author(s):

Lori A Bastian ◽

Steven P Cohen ◽

Lily Katsovich ◽

William C Becker ◽

Bradley R Brummett ◽

...

Keyword(s):

Clinical Trials ◽

Pain Management ◽

Stakeholder Engagement ◽

Military Service ◽

Work Group ◽

Pragmatic Trial ◽

Implementation Challenges ◽

Stakeholder Relationships ◽

Pragmatic Clinical Trials ◽

System Leaders

Abstract Background The NIH-DOD-VA Pain Management Collaboratory (PMC) supports 11 pragmatic clinical trials (PCTs) on nonpharmacological approaches to management of pain and co-occurring conditions in U.S. military and veteran health organizations. The Stakeholder Engagement Work Group is supported by a separately funded Coordinating Center and was formed with the goal of developing respectful and productive partnerships that will maximize the ability to generate trustworthy, internally valid findings directly relevant to veterans and military service members with pain, front-line primary care clinicians and health care teams, and health system leaders. The Stakeholder Engagement Work Group provides a forum to promote success of the PCTs in which principal investigators and/or their designees discuss various stakeholder engagement strategies, address challenges, and share experiences. Herein, we communicate features of meaningful stakeholder engagement in the design and implementation of pain management pragmatic trials, across the PMC. Design Our collective experiences suggest that an optimal stakeholder-engaged research project involves understanding the following: i) Who are research stakeholders in PMC trials? ii) How do investigators ensure that stakeholders represent the interests of a study’s target treatment population, including individuals from underrepresented groups?, and iii) How can sustained stakeholder relationships help overcome implementation challenges over the course of a PCT? Summary Our experiences outline the role of stakeholders in pain research and may inform future pragmatic trial researchers regarding methods to engage stakeholders effectively.

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The Pragmatic Turn in Clinical Research

Science & Technology Studies ◽

10.23987/sts.92043 ◽

2021 ◽

Vol 34 (2) ◽

pp. 6-24

Author(s):

Olga Zvonareva

Keyword(s):

Clinical Trials ◽

Clinical Practice ◽

Clinical Research ◽

Pragmatic Trial ◽

Limited Ability ◽

Actual Treatment ◽

Medical Experimentation ◽

Pragmatic Clinical Trials ◽

Pragmatic Turn

How does knowledge obtained in clinical trials apply to the actual treatment of patients? This question has recently acquired a new significance amidst complaints about the limited ability of trial results to improve clinical practice. Pragmatic clinical trials have been advocated to address this problem. In this article, I trace the emergence of the pragmatic turn in clinical research, starting from the first mention of ‘pragmatic trial’ in 1967, and analyse the changes to how pragmatism has been conceived. I argue that contemporary version of pragmatism risks missing the mark by focusing exclusively on establishing similarity between the trial and the clinic for the purpose of greater generalizability. This focus eclipses the move for carefully aligning medical experimentation with conditions, needs and concerns in the clinic aimed at greater usefulness.

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Design and analytic considerations for using patient-reported health data in pragmatic clinical trials: report from an NIH Collaboratory roundtable

Journal of the American Medical Informatics Association ◽

10.1093/jamia/ocz226 ◽

2020 ◽

Vol 27 (4) ◽

pp. 634-638 ◽

Cited By ~ 3

Author(s):

Frank W Rockhold ◽

Jessica D Tenenbaum ◽

Rachel Richesson ◽

Keith A Marsolo ◽

Emily C O’Brien

Keyword(s):

Clinical Trials ◽

Incomplete Data ◽

Claims Data ◽

Pragmatic Trials ◽

End Points ◽

Data Alignment ◽

Pragmatic Clinical Trials ◽

Patient Reported ◽

Reported Health ◽

Reported Data

Abstract Pragmatic clinical trials often entail the use of electronic health record (EHR) and claims data, but bias and quality issues associated with these data can limit their fitness for research purposes particularly for study end points. Patient-reported health (PRH) data can be used to confirm or supplement EHR and claims data in pragmatic trials, but these data can bring their own biases. Moreover, PRH data can complicate analyses if they are discordant with other sources. Using experience in the design and conduct of multi-site pragmatic trials, we itemize the strengths and limitations of PRH data and identify situational criteria for determining when PRH data are appropriate or ideal to fill gaps in the evidence collected from EHRs. To provide guidance for the scientific rationale and appropriate use of patient-reported data in pragmatic clinical trials, we describe approaches for ascertaining and classifying study end points and addressing issues of incomplete data, data alignment, and concordance. We conclude by identifying areas that require more research.

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Improving pragmatic clinical trial design using real-world data

Clinical Trials ◽

10.1177/1740774519833679 ◽

2019 ◽

Vol 16 (3) ◽

pp. 273-282 ◽

Cited By ~ 4

Author(s):

Susan M Shortreed ◽

Carolyn M Rutter ◽

Andrea J Cook ◽

Gregory E Simon

Keyword(s):

Clinical Trials ◽

Trial Design ◽

Suicide Attempts ◽

Real World Data ◽

Electronic Health Record Data ◽

Pragmatic Clinical Trial ◽

Pragmatic Clinical Trials ◽

Sample Size Calculations ◽

Record Data ◽

Electronic Health

Background Pragmatic clinical trials often use automated data sources such as electronic health records, claims, or registries to identify eligible individuals and collect outcome information. A specific advantage that this automated data collection often yields is having data on potential participants when design decisions are being made. We outline how this data can be used to inform trial design. Methods Our work is motivated by a pragmatic clinical trial evaluating the impact of suicide-prevention outreach interventions on fatal and non-fatal suicide attempts in the 18 months after randomization. We illustrate our recommended approaches for designing pragmatic clinical trials using historical data from the health systems participating in this study. Specifically, we illustrate how electronic health record data can be used to inform the selection of trial eligibility requirements, to estimate the distribution of participant characteristics over the course of the trial, and to conduct power and sample size calculations. Results Data from 122,873 people with patient health questionnaire (PHQ) responses, recorded in their electronic health records between 1 July 2010 and 31 March 2012, were used to show that the suicide attempt rate in the 18 months following completion of the questionnaire varies by response to item nine of the PHQ. We estimated that the proportion of individuals with a prior recorded elevated PHQ (i.e. history of suicidal ideation) would decrease from approximately 50% at the beginning of a trial to about 5%, 50 weeks later. Using electronic health record data, we conducted simulations to estimate the power to detect a 25% reduction in suicide attempts. Simulation-based power calculations estimated that randomizing 8000 participants per randomization arm would allow 90% power to detect a 25% reduction in the suicide attempt rate in the intervention arm compared to usual care at an alpha rate of 0.05. Conclusions Historical data can be used to inform the design of pragmatic clinical trials, a strength of trials that use automated data collection for randomizing participants and assessing outcomes. In particular, realistic sample size calculations can be conducted using real-world data from the health systems in which the trial will be conducted. Data-informed trial design should yield more realistic estimates of statistical power and maximize efficiency of trial recruitment.

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