Category Archives: Cluster Randomized Trials

Study Design of LIRE Pragmatic Trial Published


Picture of Jerry Jarvik, MD, MPH
Jerry Jarvik, MD, MPH, Principal Investigator, LIRE Trial

Dr. Jerry Jarvik and colleagues have published an article in Contemporary Clinical Trials describing the design of the Lumbar Imaging With Reporting of Epidemiology (LIRE) pragmatic cluster randomized trial. LIRE is one of the NIH Collaboratory’s pragmatic clinical trial Demonstration Projects, which are intended to help establish proof of concept for pragmatic trial designs.

LIRE is studying the effect of inserting epidemiologic benchmarks for common imaging findings into lumbar spine imaging reports being delivered to primary care physicians. The primary goal is to measure whether the intervention reduces subsequent spine-related tests and treatments. All outcomes are captured passively through the electronic health record. The authors state that if successful, such a low-cost intervention could potentially be applied to diagnostic tests for other conditions. LIRE has a projected sample size of more than 160,000 patients across an estimated >2000 primary care physicians at 4 health systems. Enrollment will continue through 2016.

“LIRE is a pragmatic cluster randomized trial of a minimal-risk intervention that we believe can serve as a model for future pragmatic trials.”
(Jarvik JG, et al. Contemp Clin Trials 2015)


New Biostatistical Guidance Document Available: Small-Sample Robust Variance Correction for GEE

Tools for ResearchThe NIH Collaboratory’s Biostatistics and Study Design Core has just published a new guidance document by Andrea Cook, PhD, of the Group Health Research Institute, on using small-sample robust variance correction for generalized estimating equations (GEE) for use in cluster-randomized trials. The document, which includes guidance on methods available in the SAS and Stata statistical analysis packages, is available directly from the NIH Collaboratory Knowledge Repository here (opens as PDF), or via the Biostatistical Guidance Documents page in the Living Textbook.

This guidance document is one in a series of research tools focused on detailed aspects of statistical design for conducting pragmatic clinical trials. Each document in this series provides a synthesis of current developments, discusses possible future directions, and, where appropriate, makes recommendations for application to pragmatic clinical research.


Cluster Randomized Trial Design Featured in JAMA’s Guide to Statistics and Methods Series


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.

Groundbreaking Suicide Prevention Trial has Enrolled Initial Patients

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.

Over the next 5 years, the team plans to enroll 19,500 adult patients. The study is an NIH Collaboratory Demonstration Project being overseen by the National Institute of Mental Health (NIMH).

Congratulations to Dr. Simon and his team for their achievement!

 

Report from NIH Collaboratory Workshop Examines Ethical and Regulatory Challenges for Pragmatic Cluster Randomized Trials

A new article by researchers from the NIH Collaboratory, published online this week in the journal Clinical Trials, explores some of the challenges facing physicians, scientists, and patient groups who are working to develop innovative methods for performing clinical trials. In the article, authors Monique Anderson, MD, Robert Califf, MD, and Jeremy Sugarman, MD, MPH, MA, describe and summarize discussions from a Collaboratory workshop on ethical and regulatory issues relating to pragmatic cluster-randomized trials.


Pragmatic Cluster-Randomized Trials

Many of the clinical trials that evaluate the safety and effectiveness of new therapies do so by assigning individual volunteers to receive either an experimental treatment or a comparator, such as an existing alternative treatment, or a placebo. However, this process can be complex, expensive, and slow to yield results. Further, because these studies often take place in specialized research settings and involve patients who have been carefully screened, there are  concerns that the results gathered from such trials may not be fully applicable to “real-world” patient populations.

For these reasons, some researchers, patients, and patient advocacy groups are interested in exploring different methods for conducting clinical trials, including designs known as pragmatic cluster-randomized trials, or CRTs. In a pragmatic CRT, groups of individuals (such as a clinic, hospital, or even an entire health system) are randomly assigned to receive one of two or more interventions being compared, with a focus on answering questions about therapies in the setting of actual clinical practice—the “pragmatic” part of “pragmatic CRT.”

Pragmatic CRTs have the potential to answer important questions quickly and less expensively, especially in an era in which patient data can be accessed directly from electronic health records. Just as importantly, that knowledge can then be fed back to support a “learning healthcare system” that is constantly improving in its approach to patient care.  However, while cluster-randomized trials are not themselves new, their widespread use in patient-care settings raises a number of potential challenges.

For example: in a typical individually randomized clinical trial, patients are enrolled in a study only after first providing written informed consent. However, in a CRT, the entire hospital may be assigned to provide a given therapy. In such a situation, how should informed consent be handled? How should patients be notified that research is taking place, and that they may be part of it? Will they be able to “opt out” of the research? What will happen to the data collected during their treatment? And what do federal regulations governing clinical trials have to say about this? These are just a few of the questions raised by the use of pragmatic CRTs in patient-care settings.


The NIH Collaboratory Workshop on Pragmatic Cluster-Randomized Trials

The NIH Collaboratory Workshop of Pragmatic CRTs, held in Bethesda, Maryland in July of 2103, convened a panel of experts in clinical trials, research ethics, and regulatory issues to outline the challenges associated with conducting  pragmatic CRTs and to explore ways for better understanding and overcoming them. Over the course of the intensive 1-day workshop, conference participants identified key areas for focused attention. These included issues relating to informed consent, patient privacy, oversight of research activities, insuring the integrity of data gathered during pragmatic CRTs, and special protections for vulnerable patient populations. The article by Anderson and colleagues provides a distillation of discussions that took place at the workshop, as well as noting possible directions for further work.

In the coming months and years, the NIH Collaboratory and its partners, including the National Patient-Centered Clinical Research Network (PCORnet), plan to build on this workshop experience. Together, they hope to explore these issues in greater detail and propose practical steps for moving forward with innovative clinical research methods, while at the same time maintaining robust protections for patients’ rights and well-being.


Jonathan McCall, MS, and Karen Staman, MS, contributed to this post.


Read the full text of the article here:

Anderson ML, Califf RM, Sugarman J. Ethical and regulatory issues of pragmatic cluster randomized trials in contemporary health systems. Clin Trials 2015 [e-Pub ahead of press].
doi:10.1177/1740774515571140 
For further reading:

Tunis SR, Stryer DB, Clancy CM. Practical clinical trials: Increasing the value of clinical research decision making in clinical and health policy. JAMA 2003;290(12):1624-32. PMID:14506122; doi:10.1001/jama.290.12.1624.

The Ottawa Hospital Research Institute Ethical Issues in Cluster Randomized Trials Wiki.

Special Report: Ethical Oversight of Learning Health Systems. Hastings Center Report 2013;43(s1):S2–S44, Si–Sii.

Sugarman J, Califf RM. Ethics and regulatory complexities for pragmatic clinical trials. JAMA 2014;311(23):2381-2. PMID: 24810723; doi: 10.1001/jama.2014.4164.

Collaboratory Biostatistics and Study Design Core Releases Guidance Documents


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.

The guidance documents are available through the Living Textbook and can be accessed on the “Tools for Research” tab or directly here.


Collaboratory Investigators Publish Article on Ethical and Regulatory Complexities for Pragmatic Clinical Trials in JAMA


“Ethics and Regulatory Complexities for Pragmatic Clinical Trials,” a Viewpoint article by Jeremy Sugarman, MD, MPH, MA, and Robert Califf, MD, was published online in JAMA today. In the article, the authors draw on early experiences from two large networks conducting pragmatic clinical trials, the NIH Collaboratory and the National Patient-Centered Clinical Research Network (PCORnet), to describe 10 ethical and regulatory complexities facing this new field of research. Topics covered include informed consent, risk determination, the role of gatekeepers, and institutional review board review and oversight, among others, as well as the ongoing need for further discussion and research as a key part of efforts aimed at creating a learning healthcare system.

Dr. Sugarman is chair of the Regulatory/Ethics Core of the NIH Collaboratory and deputy director for medicine of the Johns Hopkins Berman Institute of Bioethics. Dr. Califf is the principal investigator of the NIH Collaboratory Coordinating Center and director of the Duke Translational Medicine Institute.


Collaboratory’s Susan Huang receives research achievement award from Clinical Research Forum


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.

Susan Huang, MD, MPH
Susan Huang, MD, MPH

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!


LIRE Pragmatic Clinical Trial Begins Randomization



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 principal investigator of the LIRE trial is Dr. Jeffrey Jarvik  of the University of Washington. You can read more about the LIRE trial here.


SACHRP Meeting to Discuss Research Consent Issues


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.