Category Archives: Pragmatic clinical trials

Groundbreaking Suicide Prevention Trial has Enrolled Initial Patients

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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

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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.

Office for Human Research Protections Releases Draft Guidance on Disclosing Risks in Standard-of-Care Research

Comparative Effectiveness Research, Informed Consent, Pragmatic clinical trials, Regulatory issues, , , ,

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.​

 

Collaboratory Phenotypes, Data Standards, and Data Quality Core Releases Data Quality Assessment White Paper

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The NIH Collaboratory’s Phenotypes, Data Standards, and Data Quality Core has released a new white paper on data quality assessment in the setting of pragmatic research. The white paper, titled Assessing Data Quality for Healthcare Systems Data Used in Clinical Research (V1.0) provides guidance, based on the best available evidence and practice, for assessing data quality in pragmatic clinical trials (PCTs) conducted through the Collaboratory. Topics covered include an overview of data quality issues in clinical research settings, data quality assessment dimensions (completeness, accuracy, and consistency), and a series of recommendations for assessing data quality. Also included as appendices are a set of data quality definitions and review criteria, as well as a data quality assessment plan inventory.

The full text of the document can be accessed through the “Tools for Research” tab on the Living Textbook or can be downloaded directly here (PDF).

Collaboratory Biostatistics and Study Design Core Releases Guidance Documents

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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.

PCORI Executive Director Dr. Joe Selby to Speak on Regulatory Issues Concerning Big Data

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The meeting of the Secretary’s Advisory Committee for Human Research Protections (SACHRP) scheduled for July 21-22, 2014, will include a session on “Regulatory Issues Concerning Big Data.” Joe Selby, MD, MPH, executive director of the Patient-Centered Outcomes Research Institute (PCORI), will speak, along with leaders from the NIH and FDA. The session is scheduled for 1:30-3:45 pm on Monday, July 21.

SACHRP provides recommendations on human subjects protection to the Secretary of the U.S. Department of Health and Human Services and reviews activities of the Office for Human Research Protections (OHRP). Other topics to be covered during the two-day meeting include informed consent comprehension, the return of research results to human subjects, and ethical/regulatory issues in interventional social media research.

The meeting is available to the public and will be videocast live.

View the meeting agenda
View the live webcast (available July 21-22, 2014)

A link to materials from the meeting will be provided in an update to this post when available.

New Living Textbook Chapter – Electronic Health Records-Based Phenotyping

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A new Living Textbook topic chapter, “Electronic Health Records-Based Phenotyping,” has just been published. The chapter defines computable phenotypes and describes their role in data queries of electronic health records as part of pragmatic clinical trials. A main focus of the chapter is outlining mechanisms for identifying and evaluating phenotype definitions, with particular emphasis on standardization efforts of the NIH Collaboratory, including the Table 1 Project. Also included are links to recommended phenotype definitions from the Collaboratory Phenotypes, Data Standards, and Data Quality Core.

Developing Approaches to Conducting Randomized Trials Using Mini-Sentinel: Webinar and White Paper

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A recent webinar (see recording) covered a collaborative effort of the Clinical Trials Transformation Initiative (CTTI) and the FDA Mini-Sentinel project in which investigators are exploring the possibility of using the Mini-Sentinel distributed database infrastructure to conduct randomized, multicenter clinical trials. Speakers Richard Platt, MD, MS, of Harvard Pilgrim Health Care Institute, and Patrick Archdeacon, MD, of the FDA, summarized the work and discussed next steps that will continue to advance the project.

A white paper published earlier this year, Developing Approaches to Conducting Randomized Trials Using the Mini-Sentinel Distributed Database, describes the results of the investigator analysis in greater detail. The white paper is the product of the CTTI Uses of Electronic Data project.

New Living Textbook Chapter – Learning Healthcare Systems

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A new Living Textbook topic chapter, “Learning Healthcare Systems,” has just been published. The topic includes background information on the creation and evolution of the concept of the learning healthcare system and the key attributes that define such systems, as described by the Institute of Medicine:

A learning healthcare system is [one that] is designed to generate and apply the best evidence for the collaborative healthcare choices of each patient and provider; to drive the process of discovery as a natural outgrowth of patient care; and to ensure innovation, quality, safety, and value in health care [1].

Also included in the topic chapter are ethical and regulatory implications for learning healthcare systems, patient and public engagement, the application of electronic heatlh records and other information technology, logistical and organizational challenges to bulding learning healthcare systems, and early examples of such systems in practice.

Reference

1. Institute of Medicine. The Learning Healthcare System: Workshop Summary. Olsen L, Aisner D, McGinnis JM, eds. Washington, DC: National Academies Press; 2007. Available at: http://www.iom.edu/Reports/2007/The-Learning-Healthcare-System-Workshop-Summary.aspx. Accessed April 4, 2014.

PCORnet: “Not your father’s clinical trial network”

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“PCORnet: Turning a Dream Into Reality,” an editorial published online this week in the Journal of the American Medical Informatics Association, details the promises of the National Patient-Centered Clinical Research Network (PCORnet):

“Providing accurate answers based on the highest levels of scientific evidence for the majority of unresolved clinical questions is a revolutionary dream shared by patients, providers, payers, health plans, researchers, and policy makers alike. PCORnet, the National Patient-Centered Clinical Research Network, promises a transformative platform that will turn this revolutionary dream into reality.”

The authors describe PCORnet’s patient-centered vision and how its transformative clinical research will be carried out through a national research network involving both Clinical Data Research Networks and Patient-Powered Research Networks. This “network of networks” is designed to include a large, highly representative population. PCORnet will first work to establish data architecture and standards and address key policy questions, followed by the conduct of its first pragmatic clinical trial slated to begin in September 2015.

Editorial authors include NIH Director Dr. Francis Collins and PCORnet Steering Committee members Kathy L. Hudson, PhD, and Josephine P. Briggs, MD.