Dr. Kevin Weinfurt and colleagues in the Regulatory/Ethics Core of the NIH Collaboratory recently published an article in the American Journal of Bioethics regarding how acceptable different approaches to notification and authorization are to potential participants in pragmatic research. The authors conducted a series of interviews using 24 different hypothetical scenarios reflecting different types of studies and approaches to notification and authorization.
Key findings:
People have significant difficulty understanding 1) randomization and 2) that all the data are collected during routine care, and no extra visits or tests are required.
For some types of pragmatic research, many of the respondents viewed
Active alternatives to written consent—such as oral consent—as acceptable.
Less active approaches to notification—such as no notification ahead of time or broad notification—as unacceptable.
When using written consent in cases where researchers are testing accepted medical interventions that have known clinical risks but with no incremental risks of participating in the research, it was acceptable to omit the clinical risks from the consent documents, thereby shortening the forms.
A significant portion (28-49%) of respondents would decline to participate regardless of notification approach, which could lead to non-trivial consent bias (in other words, there could be significant differences in people who decline vs people who agree to participate).
Based on these findings, the authors suggest alternate approaches to notification and authorization should be further developed and tested.
The National Institutes of Health’s Office of Disease Prevention (ODP) has just released a free, self-paced online course on designing and analyzing pragmatic and group-randomized trials. The course, which is presented by ODP Director Dr. David Murray, includes a series of seven video presentations plus slide sets, reference materials, and guided activities.
Course segments typically last 25 to 35 minutes. Presentations can be accessed individually and include the following topics:
Course presenter Dr. David Murray, Director, Office of Disease Prevention, NIH (image courtesy NIH)
A new funding opportunity announcement from the NIH solicits applications to support Demonstration Projects that include an efficient, large-scale pragmatic clinical trial. Trials must be conducted across two or more health care systems (HCS) and must be conducted as part of the NIH HCS Research Collaboratory supported through the NIH Common Fund. Awards made through this FOA will initially support a one-year milestone-driven planning phase (UG3), with possible rapid transition to the second implementation phase (UH3) for a pragmatic trial Demonstration Project.
Important Due Dates Earliest submission date: May 2, 2017 Letter of intent date: 30 days prior to application due date Application due date: June 2, 2017
The ABATE Infection trial, an NIH Collaboratory project led by Dr. Susan Huang, is featured in the September 12 Health section of the Wall Street Journal. The article describes several studies aimed at preventing the hospital-associated infection MRSA (methicillin-resistant Staphylococcus aureus).
In the Reduce MRSA trial, published in 2013, Dr. Huang’s team demonstrated that treating ICU patients with a germ-fighting soap plus a nasal antibiotic ointment, an approach called “universal decolonization,” was superior to standard approaches in preventing MRSA infections. The ABATE Infection trial examines similar approaches to decolonization for all patients in non–critical care medical and surgical units, comparing the use of an antiseptic bath and nasal ointment to standard bathing and showering. More than 1 million showers and baths were taken over the course of the study, which has now completed enrollment. Data from ABATE are currently being analyzed, with the results expected to inform whether this strategy is effective in reducing hospital-associated infections.
“These are preventable infections and we should be able to drive them down to zero.” Susan Huang, MD
In the systematic review, the researchers found that imaging findings of spine degeneration are present in high proportions of asymptomatic individuals, and these findings increase with age. Thus, many degenerative features found on spine imaging are likely part of normal aging. Given that advanced imaging is increasingly used in the evaluation of patients with lower back pain, knowing the prevalence of degenerative findings in asymptomatic individuals can help clinicians and patients when interpreting imaging findings.
The LIRE pragmatic trial is testing the insertion of these epidemiologic benchmarks into lumbar spine imaging reports with the goal of reducing subsequent tests and treatments, including MRI and CT, opioid prescriptions, spinal injections, or surgery.
The study team for the Trauma Survivors Outcomes and Support (TSOS) trial recently published their study protocol in Implementation Science. TSOS, an NIH Health Care Systems Research Collaboratory Demonstration Project, is an effectiveness-implementation hybrid trial designed to test the delivery of screening and intervention for PTSD and comorbidities across 24 U.S. level I trauma center sites. The study employs a stepped-wedge, cluster-randomized design in which sites are randomized sequentially to initiate the intervention. The study aims to determine if injured patients receiving a collaborative care intervention demonstrate significant reductions in PTSD symptoms when compared with control patients receiving usual care. The study will also evaluate whether intervention patients demonstrate significant reductions in depressive symptoms and associated suicidal ideation, alcohol use problems, and improvements in physical function.
On Tuesday, May 10, 2016, the NIH Collaboratory invites you to view a public webcast of the workshop, Ethical and Regulatory Issues of Pragmatic Clinical Trials.
This workshop will include several topics from a series of articles discussing regulatory and ethical issues related to the conduct of pragmatic clinical trials. Panelists from the NIH Collaboratory pragmatic trial Demonstration Projects, along with experts in the areas of informed consent, vulnerable populations, IRBs, data monitoring committees, and privacy issues, will participate in moderated discussion using case examples from the NIH Collaboratory.
In a recent post on the FDA’s “FDA Voice” blog, Associate Deputy Commissioner Rachel Sherman and Commissioner Robert Califf describe how to overcome barriers to data sharing and create a successful national system for medical evidence generation (or “EvGen”). To foster new approaches for creating clinical evidence the authors suggest 3 principles:
“1. There must be a common approach to how data is presented, reported and analyzed and strict methods for ensuring patient privacy and data security.
2. Rules of engagement must be transparent and developed through a process that builds consensus across the relevant ecosystem and its stakeholders.
3. To ensure support across a diverse ecosystem that often includes competing priorities and incentives, the system’s output must be intended for the public good and be readily accessible to all stakeholders.”
Drs. Sherman and Califf point to substantial pioneering work being done in secondary use of data, in which data collected for clinical care are “secondarily” used for research, including projects currently underway through the NIH Collaboratory, PCORnet, and other initiatives and networks. The experience gained from these groundbreaking efforts should provide a foundation for a national system for evidence generation.
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.
ABATE study PI Dr. Susan Huang
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.
Resources: NIH Health Care Systems Collaboratory Demonstration Project. Active Bathing to Eliminate (ABATE) Infection trial. 2014. Available at: https://www.nihcollaboratory.org/demonstration-projects/Pages/ABATE.aspx. Accessed February 2, 2015.
Huang SS, Septimus E, Moody J, et al. Randomized Evaluation of Decolonization vs. Universal Clearance to Eliminate Methicillin-Resistant Staphylococcus aureus in ICUs (REDUCE MRSA Trial). 2012. Available at: https://idsa.confex.com/idsa/2012/webprogram/Paper36049.html. Accessed December 15, 1024.
Huang SS, Septimus E, Kleinman K, et al. Targeted versus universal decolonization to prevent ICU infection. N Engl J Med 2013;368:2255–2265. PMID: 23718152. doi: 10.1056/NEJMoa1207290.
A new article published in Circulation by a group of authors from the Duke Clinical Research Institute describes tensions between pragmatic clinical trial design and Good Clinical Practice (GCP) guidelines, which were established in 1996 to help ensure the safety of participants in clinical trials and the validity of trial findings. Pragmatic clinical trials (PCTs) are designed to test interventions in real-world settings and populations rather than under highly controlled conditions, and thus rely on simplified procedures, such as those used for screening, informed consent, and participant follow-up.
The authors concede that many PCT features appear to be at odds with GCP guidance, which has arguably led to improvements in the consistency and quality of trial conduct. However, they also note data suggesting that the intensive approach to monitoring and documentation fostered by GCP may ultimately increase trial cost and complexity by emphasizing minutia that “may direct focus away from critical aspects of trial conduct.”
The authors go on to suggest that GCP guidance should be updated to account for a growing proportion of research that incorporates aspects of pragmatic trial design and is conducted with data gathered from electronic health records and registries. They also offer a path forward for pragmatic research under current GCP guidelines by outlining strategies for areas that include participant enrollment, monitoring, study visits, participant follow-up, and documentation.
The authors conclude that collaborative efforts from trial sponsors, regulators, clinical trialists, and patients will be necessary to realign the guidance with contemporary trial conduct while preserving its central goal of protecting trial participants.
