Real-world data: routinely collected information about a person’s health status in the electronic health record, claims, registries, and other sources, including patient-generated sources.
Real-world evidence: reliable, clinical information derived from real-world data about risks, benefits, and burdens of therapies.
This framework will apply to various pragmatic clinical trials embedded in health care systems and conducted as part of routine care (and will not apply to more traditional clinical trials conducted parallel to care).
Three main considerations are included in the framework:
Will the real-world data be fit for use (do they reliably and adequately represent the concept)?
Will the evidence generated by the trial provide adequate evidence to help answer regulatory questions?
Will the conduct of the study meet FDA regulatory requirements?
The NIH has announced two new funding opportunity announcements (FOAs) for 7 or more embedded pragmatic clinical trials that address pain management and the opioid crisis. These projects will become part of the NIH Health Care Systems Research Collaboratory as phased UG3/UH3 cooperative research.
The NIH Collaboratory recently convened a workshop to explore embedded pragmatic clinical trials comparing two or more therapeutic medical interventions. These “A vs B” trials are meant to test existing, viable treatment alternatives where there is uncertainty about which treatment is best in which populations. There are unique barriers that make these types of pragmatic trials especially challenging to implement. For the workshop, a panel of experts gathered to discuss challenges and solutions regarding partnering with healthcare systems to conduct the trials, unique legal and ethical issues, and design and operational considerations. The summary of the workshop is now available: Workshop Summary: Embedded Pragmatic Clinical Trials of Therapeutic A vs. B Interventions
Embedded pragmatic clinical trials of therapeutic A vs. B interventions workshop videocast.
In the spring of 2018, the NIH Collaboratory will be welcoming a new set of Demonstration Projects and will help shepherd the new pragmatic trials through the piloting and implementation phases of their studies. In a new video in the Living Textbook, two of our seasoned principal investigators—Drs. Susan Huang and Gloria Coronado—give advice to the newcomers and other investigators new to conducting pragmatic trials.
“My greatest advice is to gain partners who are operational and have insight into particular areas—whether they be hospitals, or clinics, or nursing homes—who know about how they really work, how to best incorporate the intervention into workflow, how to get the right approvals, and how to get the best information technology support available to them.”—Susan Huang, MD
“One of the key things that we’ve received from being part of the Collaboratory—compared to an R01 grant—is the opportunity to interact across all of the institutes at NIH as well as learn about other projects that are working in pretty diverse health systems, including hospital systems, nursing homes, and dialysis centers.” —Gloria Coronado, PhD
Congratulations to Dr. Jeffrey Jarvik and his colleagues at the University of Washington for their recent grant award to establish the Core Center for Clinical Research (CCCR). The initiative will promote pragmatic, multi-institutional clinical research on musculoskeletal conditions, such as the diagnosis and treatment of back pain. The new center—the UW Center for Clinical Learning, Effectiveness And Research (CLEAR)—will investigate the effectiveness of interventions such as imagining tests, physical therapy, opioids, spine injections, and spine surgery, as well as approaches for implementation. The National Institutes of Health (NIH)/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) are funding the 5-year, $3.7 million initiative, which will include pragmatic and comparative effectiveness trials and Core groups, including:
The Methodology Core, led by Patrick J. Heagerty PhD, Chair of the Department of Biostatistics, and Sean Mooney PhD, Professor of Biomedical Informatics and Chief Research Information Officer
The Resource Core, led by Janna Friedly MD, Associate Professor of Rehabilitation Medicine, and Danielle Lavallee PharmD PhD, Research Associate Professor of Surgery
In an article published in Annals of Internal Medicine, authors from the NIH Collaboratory describe concerns and solutions regarding data sharing and embedded research. Pragmatic research embedded in health systems uses data from the electronic health record and comes from a fundamentally different context than explanatory trials, which collect research-specific data. Data from embedded research have the potential to do harm if taken out of context or used for comparisons. Therefore, while the authors enthusiastically support data sharing, they also recognize that mandating data sharing may discourage health systems from volunteering to participate in embedded research.
“In an ideal world of transparency regarding healthcare processes and outcomes, health systems would have no expectation of or need for privacy regarding quality of health care delivery. But the current world is not perfect, and unintentional disclosures from participation in embedded research could be far greater than that required for public quality measures. Health systems volunteering to participate in research to improve public health may not be willing to bear the additional risk of misuse of sensitive information.” — Simon et al. Ann Intern Med
The authors use examples from the NIH Collaboratory Demonstration Projects to illustrate potential solutions, and emphasize that data sharing plans for embedded research should be developed in partnership with health system leaders in ways that maximize the amount of data that can be shared while protecting patient privacy and healthcare system interests.
The NIH Collaboratory Regulatory/Ethics Core has published a charter template that can be used to help establish a data monitoring committee (DMC) and associated procedures appropriate for oversight of pragmatic clinical trials. DMCs play an important role in protecting the welfare of trial participants and ensuring the integrity of a trial so that it can yield useful results. A charter defines the primary responsibilities of a DMC, its membership, the purpose and timing of its meetings, and its procedures and statistical monitoring guidelines.
In addition to procedures and guidance for DMCs generally, this new charter template contains suggested practices specifically for DMCs for pragmatic clinical trials, such as the recommendation that at least one DMC member have prior experience in conducting and interpreting data from this type of trial.
The charter template can be downloaded and customized by organizations to set up DMCs for pragmatic clinical trials and clearly outline their operations. For more information on special considerations in data and safety monitoring for pragmatic clinical trials, please see the Data and Safety Monitoring Living Textbook chapter.
The Active Bathing to Eliminate (ABATE) Infection trial (ClinicalTrials.gov #NCT02063867) has completed its intervention phase—the first NIH Health Care Systems Research Collaboratory UH3 Demonstration Project to reach this major milestone. The large-scale, cluster-randomized pragmatic clinical trial (PCT) was designed to assess an approach for reducing multidrug-resistant organisms and hospital-associated infections (HAIs) in nearly 200 non-critical care hospital units affiliated with Hospital Corporation of America (HCA) across the United States.
The ABATE study is led by principal investigator Dr. Susan Huang of the University of California, Irvine, who stated “We are elated to reach the successful completion of the trial thanks to an incredible investigative team at HCA, Harvard Pilgrim Health Care, Rush University, the University of Massachusetts Amherst, and UC Irvine. We look forward to what the trial data will tell us and hope that we can continue to find effective ways to protect patients from infection.”
In the ABATE study, patients hospitalized in non-critical care units were bathed either according to the hospital unit’s usual care procedures (the control group) or bathed with the topical antibacterial agent chlorhexidine (plus nasal administration of the antibiotic mupirocin for those patients who were colonized or infected with, or had a history of methicillin-resistant Staphylococcus aureus [MRSA] [the intervention group]). The study investigators will compare the number of unit-attributable, multidrug-resistant organisms in clinical cultures between the study arms; these organisms include vancomycin-resistant enterococci (VRE), MRSA, and gram-negative bacteria. In addition, the investigators will compare the number of unit-attributable infections in the bloodstream and urinary tract (all pathogens) and Clostridium difficile infections. Cultures were collected at baseline and post intervention and will be assessed to determine whether resistance emerged to decolonization products.
“We are elated to reach the successful completion of the trial thanks to an incredible investigative team at HCA, Harvard Pilgrim Health Care, Rush University, the University of Massachusetts Amherst, and UC Irvine.We look forward to what the trial data will tell us and hope that we can continue to find effective ways to protect patients from infection.”
Healthcare-associated infections caused by common bacteria, including MRSA and VRE, are a leading cause of preventable illness and death in the United States and are associated with upward of $6.5 billion in annual healthcare costs. Although these bacteria normally live on the skin or in the nose, under certain circumstances they can cause serious or even life-threatening infections. Hospitalized patients who are ill or who have weakened immune systems are especially at risk for such infections. Because these pathogens are resistant to many antibiotics, they can be difficult to treat.
In intensive care units (ICUs), reducing the amount of such bacteria (a process referred to as decolonization) by treating patients’ skin with chlorhexidine and their noses with mupirocin ointment has been shown to reduce MRSA infections and all-cause bacteremias. However, relatively little is known about the effects of decolonization in hospital settings outside of critical care units, although this is where the majority of such infections occur. The ABATE trial, in contrast, is testing its bathing and decolonization strategy in adult medical, surgical, oncology, and step-down units (pediatric, psychology, peri-partum, and bone marrow transplantation units were excluded).
Over the course of the study, more than a million showers and baths were taken, and all sites have completed the intervention. The next steps for the ABATE investigators are to finish strain collection over the coming weeks, and then clean, validate, and analyze the data over the coming months.
In contrast to traditional randomized controlled clinical trials where data are prospectively collected, many pragmatic clinical trials use data that were primarily collected for clinical purposes and are secondarily used for research. The chapter describes the steps a prospective researcher will take to acquire and use EHR data:
Gain permission to use the data. When a prospective researcher wishes to use data, a data use agreement (DUA) is usually required that describes the purpose of the research and the proposed use of the data. This section also describes use of de-identified data and limited data sets.
Understand fundamental differences in context. Data collected in routine care settings reflect standard procedures at an individual’s healthcare facility, and are not collected in a standard, structured manner.
Assess the availability of health record data. Few assumptions can be made about what is available from an organization’s healthcare records; up-front, detailed discussions about data element collection over time at each facility is required.
Understand the available data. A secondary data user must understand both the data meaning and the data quality; both can vary greatly across organizations and affect a study’s ability to support research conclusions.
Identify populations and outcomes of interest. Because healthcare facilities are obligated to provide only the minimum necessary data to answer a research question, investigators must identify the needed patients and data elements with specificity and sensitivity to answer the research question given the available data.
Consider record linkage. Studies using data from multiple records and sources will require matching data to ensure they refer to the correct patient.
Manage the data. The investigator is responsible for receiving, managing, and processing data and must demonstrate that the data are reproducible and support research conclusions.
Archive and share the data after the study. Data may be archived and shared to ensure reproducibility, enable auditing for quality assurance and regulatory compliance, or to answer other questions about the research.