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Objective We identified challenges and solutions to using electronic health record (EHR) systems for the design and conduct of pragmatic research. Materials and Methods Since 2012, the Health Care Systems Research Collaboratory has served as the resource coordinating center for 21 pragmatic clinical trial demonstration projects. The EHR Core working group invited these demonstration projects to complete a written semistructured survey and used an inductive approach to review responses and identify EHR-related challenges and suggested EHR enhancements. Results We received survey responses from 20 projects and identified 21 challenges that fell into 6 broad themes: (1) inadequate collection of patient-reported outcome data, (2) lack of structured data collection, (3) data standardization, (4) resources to support customization of EHRs, (5) difficulties aggregating data across sites, and (6) accessing EHR data. Discussion Based on these findings, we formulated 6 prerequisites for PCTs that would enable the conduct of pragmatic research: (1) integrate the collection of patient-centered data into EHR systems, (2) facilitate structured research data collection by leveraging standard EHR functions, usable interfaces, and standard workflows, (3) support the creation of high-quality research data by using standards, (4) ensure adequate IT staff to support embedded research, (5) create aggregate, multidata type resources for multisite trials, and (6) create re-usable and automated queries. Conclusion We are hopeful our collection of specific EHR challenges and research needs will drive health system leaders, policymakers, and EHR designers to support these suggestions to improve our national capacity for generating real-world evidence.

BACKGROUND: Ethical responsibilities for monitoring and responding to signals of behavioral and mental health risk (such as suicidal ideation, opioid use disorder, or depression) in general clinical research have been described; however, pragmatic clinical trials (PCTs) raise new contextual challenges. METHODS: We use our experience with the PRISM (Pragmatic and Implementation Studies for the Management of Pain to Reduce Opioid Prescribing) program, which is a component of the Helping End Addiction Long-Term (HEAL) Initiative, to provide examples of research studying nonpharmacologic interventions for pain that collect sensitive data. Members of the PRISM Ethics and Regulatory Core and Patient-Centered Outcome Core Working Group discussed and refined considerations and recommendations. RESULTS: PCT researchers can help identify the extent of their ethical obligations to monitor and respond to signals of potential behavioral and mental health risks by understanding and aligning stakeholder expectations; considering characteristics of the trial and study population; defining triggers, thresholds, and responsibilities for action; identifying appropriate response mechanisms and capabilities; integrating responses with health systems; and addressing privacy. Based on such an assessment, researchers should proactively identify if, when, and how a response will be triggered. Doing so necessitates that stakeholders understand their roles in managing such risks. Finally, consent forms and other study disclosures should clearly state what if any responses might be taken. CONCLUSION: Early and ongoing bi-directional communication with relevant stakeholders is critical to identifying and meeting the ethical challenges for PCTs when managing and responding to behavioral and mental health data that potentially signal elevated risk to individuals.

© 2017 The Author(s). Background: The clinical research enterprise is not producing the evidence decision makers arguably need in a timely and cost effective manner; research currently involves the use of labor-intensive parallel systems that are separate from clinical care. The emergence of pragmatic clinical trials (PCTs) poses a possible solution: these large-scale trials are embedded within routine clinical care and often involve cluster randomization of hospitals, clinics, primary care providers, etc. Interventions can be implemented by health system personnel through usual communication channels and quality improvement infrastructure, and data collected as part of routine clinical care. However, experience with these trials is nascent and best practices regarding design operational, analytic, and reporting methodologies are undeveloped. Methods: To strengthen the national capacity to implement cost-effective, large-scale PCTs, the Common Fund of the National Institutes of Health created the Health Care Systems Research Collaboratory (Collaboratory) to support the design, execution, and dissemination of a series of demonstration projects using a pragmatic research design. Results: In this article, we will describe the Collaboratory, highlight some of the challenges encountered and solutions developed thus far, and discuss remaining barriers and opportunities for large-scale evidence generation using PCTs. Conclusion: A planning phase is critical, and even with careful planning, new challenges arise during execution; comparisons between arms can be complicated by unanticipated changes. Early and ongoing engagement with both health care system leaders and front-line clinicians is critical for success. There is also marked uncertainty when applying existing ethical and regulatory frameworks to PCTS, and using existing electronic health records for data capture adds complexity.

While conducting a set of large-scale multi-site pragmatic clinical trials involving high-impact public health issues such as end-stage renal disease, opioid use, and colorectal cancer, there were substantial changes to both policies and guidelines relevant to the trials. These external changes gave rise to unexpected challenges for the trials, including decisions regarding how to respond to new clinical practice guidelines, increased difficulty in implementing trial interventions, achieving separation between treatment groups, and differential responses across sites. In this article, we describe these challenges and the approaches used to address them. When deliberating appropriate action in the face of external changes during a pragmatic clinical trial, we recommend considering the well-being of the participants, clinical equipoise, and the strength and quality of the evidence associated with the change; involving those charged with data and safety monitoring; and where possible, planning for potential external changes as the trial is being designed. Any solution must balance the primary obligation to protect the well-being of participants with the secondary obligation to protect the integrity of the trial in order to gain meaningful answers to important public health questions.

Pragmatic research that compares interventions to improve the organization and delivery of health care may overlap, in both goals and methods, with quality improvement activities. When activities have attributes of both research and quality improvement, confusion often arises about what ethical oversight is, or should be, required. For routine quality improvement, in which the delivery of health care is modified in minor ways that create only minimal risks, oversight by local clinical or administrative leaders utilizing institutional policies may be sufficient. However, additional consideration should be given to activities that go beyond routine, local quality improvement to first determine whether such non-routine activities constitute research or quality improvement and, in either case, to ensure that independent oversight will occur. This should promote rigor, transparency, and protection of patients’ and clinicians’ rights, well-being, and privacy in all such activities. Specifically, we recommend that (1) health care organizations should have systematic policies and processes for designating activities as routine quality improvement, non-routine quality improvement, or quality improvement research and determining what oversight each will receive. (2) Health care organizations should have formal and explicit oversight processes for non-routine quality improvement activities that may include input from institutional quality improvement experts, health services researchers, administrators, clinicians, patient representatives, and those experienced in the ethics review of health care activities. (3) Quality improvement research requires review by an institutional review board; for such review to be effective, institutional review boards should develop particular expertise in assessing quality improvement research. (4) Stakeholders should be included in the review of non-routine quality improvement and quality improvement–related research proposals. Only by doing so will we optimally leverage both pragmatic research on health care delivery and local implementation through quality improvement as complementary activities for improving health.

Pragmatic clinical trials are designed to inform decision makers about the benefits, burdens, and risks of health interventions in real-world settings. Pragmatic clinical trials often use for research purposes data collected in the course of clinical practice. The distinctive features of pragmatic clinical trials demand fresh thinking about what is required to act properly toward people affected by their conduct, in ways that go beyond ensuring the protection of rights and welfare for “human research subjects” under conventional research ethics regulations. To stimulate such work, we propose to distinguish among categories of research participants in pragmatic clinical trials as follows: Direct participants: (1) individuals being directly intervened upon and/or (2) individuals from whom personal identifiable data are being collected for the purposes of the pragmatic clinical trial. Indirect participants: individuals who are (1) not identified as direct participants and (2) whose rights and welfare may be affected by the intervention through their routine exposure to the environment in which the intervention is being deployed. Collateral participants: patient groups and other stakeholder communities who may be otherwise affected by the occurrence and findings of the pragmatic clinical trial. We illustrate these distinctions with case examples and discuss the distinctive responsibilities of researchers and pragmatic clinical trial leadership toward each type of participant. We suggest that pragmatic clinical trial investigators, institutional review boards, health systems leaders, and others engaged in the research enterprise work together to identify these participants. For indirect participants, risks and benefits to which they are exposed should be weighed to ensure that their rights and welfare are protected accordingly, and communication strategies should be considered to help them make well-informed decisions. Collateral participants could provide input on the design, planning, and conduct of a pragmatic clinical trial and offer insights regarding the best way to communicate the trial’s results to their constituencies.

With pragmatic clinical trials, an opportunity exists to answer important questions about the relative risks, burdens, and benefits of therapeutic interventions. However, concerns about protecting the privacy of this information are significant and must be balanced with the imperative to learn from the data gathered in routine clinical practice. Traditional privacy protections for research uses of identifiable information rely disproportionately on informed consent or authorizations, based on a presumption that this is necessary to fulfill ethical principles of respect for persons. But frequently, the ideal of informed consent is not realized in its implementation. Moreover, the principle of respect for persons—which encompasses their interests in health information privacy—can be honored through other mechanisms. Data anonymization also plays a role in protecting privacy but is not suitable for all research, particularly pragmatic clinical trials. In this article, we explore both the ethical foundation and regulatory framework intended to protect privacy in pragmatic clinical trials. We then review examples of novel approaches to respecting persons in research that may have the added benefit of honoring patient privacy considerations.

OBJECTIVES We sought to examine contemporary utilization patterns and clinical outcomes in patients with acute myocardial infarction (AMI) requiring intra-aortic balloon pump (IABP) counterpulsation. BACKGROUND Despite increasing experience with and broadened indications for intra-aortic counterpulsation, the current indications, associated complications, and clinical outcomes of IABP use in AMI are unknown. METHODS Between June 1996 and August 2001, data were prospectively collected from 22,663 consecutive patients treated with aortic counterpulsation at 250 medical centers worldwide; 5,495 of these patients had AMI. RESULTS Placement of an IABP in AMI patients was most frequently indicated for cardiogenic shock (27.3%), hemodynamic support during catheterization and/or angioplasty (27.2%) or prior to high-risk surgery (11.2%), mechanical complications of AMI (11.7%), and refractory post-myocardial infarction unstable angina (10.0%). Balloon insertions were successful in 97.7% of patients. Diagnostic catheterization was performed in 96% of patients, and 83% underwent coronary revascularization before hospital discharge. The in-hospital mortality rate was 20.0% (38.7% in patients with shock) and varied markedly by indication and use of revascularization procedures. Major IABP complications occurred in only 2.7% of patients, despite median use for three days, and early IABP discontinuation was required in only 2.1% of patients. CONCLUSIONS With contemporary advances in device technology, insertion technique, and operator experience, IABP counterpulsation may be successfully employed for a wide variety of conditions in the AMI setting, providing significant hemodynamic support with rare major complications in a high-risk patient population.

Numerous advances have been made in recent years in the diagnosis and treatment of patients with acute coronary syndromes (ACS). These advances, based on clinical observations, experience, and randomized clinical trials, have led many cardiologists, emergency medicine physicians, and allied healthcare professionals to change their practices. Some physicians, however, have been slow to embrace the new trends. In fact, research shows that a wide gap exists between how evidence suggests patients with ACS should be treated and how these patients actually are treated across the United States. Since 1980, a joint task force sponsored by the American College of Cardiology (ACC) and the American Heart Association (AHA) has published guidelines for the treatment of various cardiovascular diseases. The guidelines are intended to assist healthcare professionals in making appropriate decisions about the diagnosis and management of specific conditions. The ACC/AHA guidelines for the treatment of patients with unstable angina and non-ST segment elevation ACS (NSTE ACS) were first established in 1994 by the Agency for Health Care Policy and Research, now the Agency for Healthcare Research and Quality. Since the initial publication of the guidelines, angiotensin-converting enzyme (ACE) inhibitors were shown to improve outcomes in patients with coronary artery disease (CAD), platelet glycoprotein (GP) IIb-IIIa inhibitors were shown to reduce the risk of death or nonfatal myocardial infarction (MI) in several large studies, and an early invasive management strategy was shown to reduce long-term mortality. In September 2000, the ACC and AHA jointly published new guidelines for the management of patients with unstable angina or NSTE acute MI (NSTEMI), the two conditions that collectively make up NSTE ACS. The guidelines were further updated in March 2002, based on new evidence. The treatment of patients with unstable angina or NSTEMI has changed dramatically in the past 6 years, and the changes to the guidelines reflect our growing understanding of the disease. Unstable angina and NSTEMI are deadly diseases that have major public health implications. The National Center for Health Statistics reported that in 1996 alone there were 1,433,000 hospitalizations for unstable angina and NSTEMI. Data from the Platelet Glycoprotein IIb-IIIa in Unstable Angina: Receptor SuppresAdditional material related to this article can be found on the Critical Pathways in Cardiology web site. Go to the following address, click on Article Plus button next to the article in Table of

Although the need to safeguard the confidentiality of patients whose data might be shared is widely recognized, the authors discuss the similar need to consider the risks to health care systems and...

Introduction: Self-reporting by patients though the use of electronic patient-reported outcome (PRO) measures has been shown to use increase patient satisfaction with care, and improve patient-provider communication, symptom management, and health quality. Additionally, PROs are increasingly used in research to expand understanding regarding the relative risks, benefits, and burdens of interventions. While experience embedding patient-reported outcomes (PROs) into registries and clinical workflow is growing, there is little in the literature to guide those interested in incorporating PROs into routine clinical care and for use in research.Case Descriptions: The NIH Health Care Systems Research Collaboratory PRO Core interviewed investigators from seven programs to get their first-hand experiences on the incorporation of PROs for both care and research, and the investigators have contributed to this manuscript as authors.Findings: We use these case studies to present practical approaches to initiating and implementing PROS, including instrument selection, tips for integrating PRO collection systems into clinical workflow, considerations for user experience and data collection, and the methods to assess and monitor quality.Conclusion: Because the decision to initiate and implement PRO collection impacts many different stakeholders, the solution requires collaboration among the involved parties, careful planning, and integration into clinical workflow.

In order to demonstrate that allelopathic interactions are occurring, one must, among other things, demonstrate that putative phytotoxins move from plant residues on or in the soil, the source, through the bulk soil to the root surface, a sink, by way of the rhizosphere. We hypothesized that the incorporation of phytotoxic plant residues into the soil would result in a simultaneous inhibition of seedling growth and a stimulation of the rhizosphere bacterial community that could utilize the putative phytotoxins as a sole carbon source. If true and consistently expressed, such a relationship would provide a means of establishing the transfer of phytotoxins from residue in the soil to the rhizosphere of a sensitive species under field conditions. Presently, direct evidence for such transfer is lacking. To test this hypothesis, cucumber seedlings were grown in soil containing various concentrations of wheat or sunflower tissue. Both tissue types contain phenolic acids, which have been implicated as allelopathic phytotoxins. The level of phytotoxicity of the plant tissues was determined by the inhibition of pigweed seedling emergence and cucumber seedling leaf area expansion. The stimulation of cucumber seedling rhizosphere bacterial communities was determined by the plate dilution frequency technique using a medium containing phenolic acids as the sole carbon source. When sunflower tissue was incorporated into autoclaved (to reduce the initial microbial populations) soil, a simultaneous inhibition of cucumber seedling growth and stimulation of the community of phenolic acid utilizing rhizosphere bacteria occurred. Thus, it was possible to observe simultaneous inhibition of cucumber seedlings and stimulation of phenolic acid utilizing rhizosphere bacteria, and therefore provide indirect evidence of phenolic acid transfer from plant residues in the soil to the root surface. However, the simultaneous responses were not sufficiently consistent to be used as a field screening tool but were dependent upon the levels of phenolic acids and the bulk soil and rhizosphere microbial populations present in the soil. It is possible that this screening procedure may be useful for phytotoxins that are more unique than phenolic acids.

Bulk-soil and rhizosphere bacteria are thought to exert considerable influence over the types and concentrations of phytotoxins, including phenolic acids, that reach a root surface. Induction and/or selection of phenolic acid-utilizing (PAU) bacteria within the bulk-soil and rhizosphere have been observed when soils are enriched with individual phenolic acids at concentrations ≥0.25 μmol/g soil. However, since field soils frequently contain individual phenolic acids at concentrations well below 0.1 μmol/g soil, the actual importance of such induction and/or selection remains uncertain. Common bacteriological techniques (e.g., isolation on selective media, and plate dilution frequency technique) were used to demonstrate in Cecil Ap soil systems: (1) that PAU bacterial communities in the bulk soil and the rhizosphere of cucumber seedlings were induced and/or selected by mixtures composed of individual phenolic acids at concentrations well below 0.25 μmol/g soil; (2) that readily available carbon sources other than phenolic acids, such as glucose, did not modify induction and/or selection of PAU bacteria; (3) that the resulting bacterial communities readily utilize mixtures of phenolic acids as a carbon source; and (4) that depending on conditions (e.g., initial PAU bacterial populations, and phenolic acid concentration) there were significant inverse relationships between PAU bacteria in the rhizosphere of cucumber seedlings and absolute rates of leaf expansion and/or shoot biomass. The decline in seedling growth could not be attributed to resource competition (e.g., nitrogen) between the seedlings and the PAU bacteria in these studies. The induced and/or selected rhizosphere PAU bacteria, however, reduced the magnitude of growth inhibition by phenolic acid mixtures. For a 0.6 μmol/g soil equimolar phenolic acid mixture composed of p-coumaric acid, ferulic acid, p-hydroxybenzoic acid, and vanillic acid, modeling indicated that an increase of 500% in rhizosphere PAU bacteria would lead to an approximate 5% decrease (e.g., 20–25%) in inhibition of absolute rates of leaf expansion. As far as we know, this is the first time that such a relationship has been quantified.