The National Institutes of Health (NIH) Office of Extramural Research has released new clinical trial requirements for grant applications and contract proposals due on or after January 25, 2018. In anticipation of these new requirements, the NIH modified the Application Guide and the Review Criteria to address methodological problems common to many clinical trials. As group- or cluster-randomization designs are increasingly common in both basic and applied research, the new Application Guide includes links to the new Research Methods Resources website, which provides resources for investigators considering these group- or cluster-randomized designs, including lists of NIH webinars, key references, and statements to help investigators prepare sound applications and avoid methodological pitfalls.
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.
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 this week in JAMA describes the cluster randomized trial design. The article is part of JAMA’s Guide to Statistics and Methods series, which publishes explanations of analytic and methodologic approaches used in current research articles to help clinicians better understand the research.
In “Cluster Randomized Trials: Evaluating Treatments Applied to Groups,” Drs. William J. Meurer and Roger J. Lewis define cluster randomization, describe its advantages and limitations, and provide guidance on interpreting cluster randomized trials. The article discusses aspects of a recent cluster randomized trial, the RESTORE trial, as an example.
In RESTORE, pediatric intensive care units were randomized to assess the effects of a nurse-implemented sedation protocol for children with acute respiratory failure on mechanical ventilation. As Meurer and Lewis point out, “interventions that involve training multidisciplinary health care teams are practically difficult to conduct using individual-level randomization, as health care practitioners cannot easily unlearn a new way of taking care of patients.” Cluster randomized designs are therefore often used for this type of research, and it is important for clinicians to be able to understand and evaluate these studies.
Reference: Meurer WJ, Lewis RJ. Cluster randomized trials: evaluating treatments applied to groups. JAMA. 2015;313:2068-2069. PMID: 26010636. doi:10.1001/jama.2015.5199.
March 5, 2015
Dr. Greg Simon and the Suicide Prevention Team have enrolled the first participants in the Pragmatic Trial of Population-Based Programs to Prevent Suicide Attempt. This groundbreaking study was developed by researchers at Group Health Cooperative in Seattle, Washington, Health Partners Medical Group in Minnesota, and Kaiser Permanente of Colorado, in collaboration with patients who have experienced suicidal thoughts or survived suicide attempts themselves.
Over 9 million adults in the United States experience suicidal thoughts, and more than 1 million adults attempt suicide each year. However, patients at risk for suicidal behavior are not routinely identified, and successful interventions for depression and suicide are not routinely implemented. New evidence suggests that patients who report frequent thoughts of death or self-harm on a commonly-used depression questionnaire are at higher risk for suicide attempt and death over the following year.
This study aims to address the significant problem of suicide by identifying patients who are at risk for suicidal behavior and testing two suicide prevention strategies. Patients at participating institutions will complete a standard depression severity questionnaire during routine clinical care, and the results will be stored in their electronic health records (EHR). Investigators will use the responses in the EHR to identify at-risk individuals, and once identified, the patients will be randomly assigned to either usual care or to two treatment programs. The first is a collaborative care-management approach; the second is an online skills training program called “Now Matters Now,” which is designed to help people manage painful emotions and stressful situations.
Congratulations to Dr. Simon and his team for their achievement!
On October 20, 2014 the Office for Human Research Protections (OHRP) released a draft guidance on how to apply the Department of Health and Human Services (HHS) regulations on protecting human subjects (45 CFR Part 46) who participate in research studies intended to evaluate risks of treatments or procedures commonly used by healthcare professionals and recognized as “standard of care.” In standard-of-care research (or comparative effectiveness research), participants are randomized to receive one of two (or more) treatments that are accepted by medical experts as appropriate treatments for a given disease or condition.
Because treatments assigned to some participants might be different than the treatments they would have been assigned if they were not participating in the study, and the risks associated with one treatment might be different from the risks associated with another treatment, the OHRP recommends that these risks be fully described to potential participants as a part of the informed consent process.
Click here for the full draft guidance: Draft Guidance on Disclosing Reasonably Foreseeable Risks in Research Evaluating Standards of Care
The Institute of Medicine is planning a two-day public workshop in December to discuss human subjects protections in standard-of-care research. Click here for more information.
The NIH Collaboratory’s Biostatistics and Study Design Core has released the first in a series of guidance documents focusing on statistical design issues for pragmatic clinical trials. Each of the four guidance documents are intended to help researchers by providing a synthesis of current developments in the field, discuss possible future directions, and, where appropriate, make recommendations for application to pragmatic clinical research.
Dr. Susan Huang, principal investigator for the NIH Collaboratory’s ABATE (Active Bathing To Eliminate Infection) UH3 Demonstration Project, has received a Clinical Research Achievement Award(PDF) from the Clinical Research Forum, an advocacy group that includes leaders from academia, government, industry, and private foundations.
ABATE is a cluster-randomized trial that will evaluate different strategies for preventing hospital-acquired infections, including methicillin-resistant Staphylococcus aureus (MRSA) infections, a potentially serious complication and one that is particularly dangerous in intensive care units, although MRSA is known to create problems across a wide range of settings.
Dr. Huang was one 10 winners of CRF Research Achievement Awards, which are presented annually. A key report related to the ABATE project was published in the New England Journal of Medicine in June of 2013.
Additional details of the award are available here.
Congratulations to Dr. Huang and her team!
One of the NIH Collaboratory’s initial Demonstration Projects, the Lumbar Image Reporting with Epidemiology (LIRE) study, has begun randomization in early April. The LIRE trial is designed to test whether inserting additional epidemiological information into the lumbar spine imaging reports of patients being treated for lower back pain can help both doctors and patients to better understand and interpret the reports. This in turn could help doctors avoid subjecting patients to unnecessary tests and procedures.
LIRE is a cluster randomized trial, which means that instead of randomizing individual patients, whole clinics (one at the Henry Ford Health System in Detroit; one at Group Health Cooperative in Seattle, with more to follow) are randomly assigned to provide either the experimental treatment or the control treatment to patients.
Cluster-randomized trials offer a number of advantages, including the avoidance of certain kinds of bias that can effect the outcome of a study, but they also raise special issues that can require careful consideration.
The Department of Health & Human Services’ Secretary’s Advisory Committee on Human Research Protections (SACHRP) has announced that it will be holding a 2-day public meeting centering on consent issues in clinical research.
Part of the meeting will be devoted to discussion of consent issues in the context of cluster randomized trials. Unlike “typical” clinical trials that randomly assign an individual research volunteer to receive one of two treatment options, or a treatment vs. a placebo, a cluster randomized trial (or CRT) randomly assigns groups of people to an intervention. These groups can include clinics, hospitals, city blocks, or whole healthcare systems. Because CRTs randomize groups rather than individuals, obtaining consent from the people involved in such research can present a number of challenging issues.
Meeting participants will also discuss a variety of other topics related to the application of regulations governing research conduct in the current era, as well as potential changes to such regulations.
The meeting, which will include programmed presentations as well as a period for public comment, will be held in Washington, DC, on March 12-13, 2014, at the U.S. Department of Health and Human Services, 200 Independence Avenue SW., Hubert H. Humphrey Building, Room 800. A full program of the meeting’s events is available here, and additional description and context are available from the Federal Register.
Evidence on what is effective, and under what circumstances, is often lacking, poorly communicated to decision makers, or inadequately applied, and despite significant expenditures on health care for Americans, these investments have not translated to better health.
—The Learning Healthcare System (IOM Workshop Summary), 2007
The IOM report called for a new approach to closing the existing gaps in patient care, one that would create a system in which patient care, quality improvement efforts, and clinical research would exist as integrated components within a virtuous cycle of feedback—the “learning healthcare system.” (The original report, plus a series of related reports [PDF], can be read for free online at the National Academies Press website.)
In the years since The Learning Healthcare System was first published, researchers, healthcare providers, health systems, and governmental and regulatory agencies have all struggled with the monumental task of building such a system. One aspect that has presented a particularly complex set of challenges centers on the issue of informed consent. The principle of informed consent—the idea that all patients have the right to make a fully informed decision, free from coercion or other undue pressure, about whether or not to participate in research—is a foundational tenet of clinical research ethics. However, some of the tools that are widely considered to be critical to the success of achieving a workable learning healthcare system, such comparative effectiveness studies and cluster-randomized trials, are difficult or even impossible to conduct under existing models of individual informed consent.
Recent efforts from the Ottawa Consensus Statement Group and a series of articles published in an issue of the Hastings Center Report have explored explored informed consent in such circumstances. These are now joined by a pair of articles published in the February 20, 2014 issue of the New England Journal of Medicine. In the first, Faden and colleagues outline a case for streamlining or even dispensing with individual informed consent in certain kinds of randomized comparative-effectiveness or quality improvement studies that present a minimal risk of harm to patients . The authors also describe the larger framework that would provide transparent and accountable oversight of such studies, as well as overseeing the integration of findings from such research into the patient-care process.
The second article, by Kim and Miller, presents a different vision for informed consent, the “Integrated Consent Model” . Unlike Faden and colleagues, the authors argue for preserving the element of informed consent for all randomized pragmatic research, even in circumstances considered to pose minimal risk to patients. Kim and Miller suggest that such a model, in which the prospect of participating in research is offered as part of the general clinical discussion about treatment options and documented by the physician, will satisfy ethical imperatives for informing patients while remaining sufficiently streamlined to meet the demands of pragmatic clinical research. They also argue that an “integrated consent” approach could be accommodated under existing regulations.
Regardless of whether either or both of these perspectives can be incorporated into the emerging learning healthcare system, the larger questions surrounding informed consent are garnering significant interest, as evidenced by the response to the Department of Health and Human Service’s 2011 call for public comment on a proposal to modify rules governing clinical research. And with the proliferation of new technologies and trial designs that use data extracted directly from patient’s electronic health records (such as the demonstration projects coordinated through the NIH Collaboratory) and the emergence of innovative networks devoted to pragmatic patient-centered research, the need for a solution both protects patients and enables vitally needed research will only continue to grow.
For additional perspective on the recent publications in the New England Journal of Medicine, see "Research Permissions–Angels on the Head of a Pin, or the Key Issue to Decipher?" by NIH Collaboratory PI Dr. Rob Califf.
1. Faden RR, Beauchamp TL, Kass NE. Informed consent, comparative effectiveness, and learning health care. N Engl J Med 2014;340:766-768. 10.1056/NEJMhle1313674. ↑
2. Kim SYH, Miller FG. Informed consent for pragmatic trials — The integrated consent model. N Engl J Med 2014; 370:769-772. doi: 10.1056/NEJMhle1312508. ↑