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)
On Friday of last week, the US Department of Health and Human Services published a long-awaited final rule (PDF) that governs the registration and data reporting for clinical trials with ClinicalTrials.gov. The final rule and an accompanying complementary policy issued by the National Institutes of Health (NIH) represents the formal codification and clarification of requirements first described in Section 801 of the 2007 Food and Drug Administration Amendments Act (FDAAA). These requirements oblige research sponsors or other responsible parties to register most kinds of clinical trials with an accepted, publicly available registry (such as ClinicalTrials.gov) and to report certain key data about the trial design, study population, and outcomes.
However, despite the enactment of FDAAA in 2008, compliance with many of its requirements has generally been poor, as both scholarly investigations and media reports have documented. Although registration of trials has improved during this interval, possibly due to many scientific journals refusing to publish reports from unregistered studies, basic summary data (including information about adverse events) from many clinical trials have gone unreported in the ClinicalTrials.gov registry, with academic researchers being among the worst offenders for late reporting or failure to report. In addition, although Section 801 of FDAAA includes penalties for not meeting reporting obligations, no enforcement actions have yet been taken.
The final rule, which goes into effect in January of 2017, clarifies reporting requirements and responsibilities, provides checklists for research sponsors, establishes penalties for failing to fulfill reporting obligations in a timely fashion, and obligates sponsors to furnish the full research protocol to ClincalTrials.gov. Importantly, the HHS rules and NIH policy also articulate new standards for gathering and reporting data about the race and ethnicity of trial participants—information that has often been lacking from many trials datasets.
The Clinical Trials Transformation Initiative (CTTI) has released its Annual Reportfor 2015. The report describes major achievements from the previous year, including new recommendations and related tools and checklists for improving the safety, efficiency, and overall quality of clinical research.
2015 CTTI Annual Report
Highlights of the 2015 Annual Report include recommendations on topics including:
Ethics review processes
Good Clinical Practice training for trial investigators
Research protocol design
Engagement of patient groups as equal partners in clinical research
Informed consent processes
Safety reporting systems for research participants
A public-private partnership whose many stakeholders include government agencies, advocacy groups, professional societies, academic research organizations, and representatives from the medical products industry, CTTI’s mission is to “identify and promote practices that will increase the quality and efficiency of clinical trials.”
A PDF version of the report is available here. Previous Annual Reports are also available on the CTTI website.
A new article published in the journal Trials provides a look at how the Pragmatic–Explanatory Continuum Indicator Summary, or PRECIS, rating system can be applied to clinical trials designs in order to examine where a given study sits on the spectrum of explanatory versus pragmatic clinical trials.
The PRECIS-2 criteria are used to rate study designs as more or less “pragmatic” according to multiple domains that include participant eligibility, recruitment methods, setting, organization, analysis methods, primary outcomes, and more. In this context, “pragmatic” refers to trials that are designed to study a therapy or intervention in a “real world” setting similar or identical to the one in which the therapy will actually be used. Pragmatic trials stand in contrast to explanatory trials, which are typically designed to demonstrate the safety and efficacy of an intervention under highly controlled conditions and in carefully selected groups of participants, but which may also be difficult to generalize to larger or more varied populations.
PRECIS-2 Wheel. Kirsty Loudon et al. BMJ 2015;350:bmj.h2147. Copyright 2015 by British Medical Journal Publishing Group. Used by permission.
Clinical trials are almost never wholly “explanatory” or wholly “pragmatic.” Instead, many studies exist somewhere on a spectrum between these two categories. However, understanding how these different attributes apply to trials can help researchers design studies that are optimally fit for purpose, whether that purpose is to describe a biological mechanism (as in an explanatory trial) or to show how effective an intervention is when used across a broad population of patients (as in a pragmatic trial).
In their article in Trials, authors Karin Johnson, Gila Neta, and colleagues applied PRECIS-2 criteria to 5 pragmatic clinical trials (PCTs) being conducted through the NIH Collaboratory. Each trial was found to rate as “highly pragmatic” across the multiple PRECIS-2 domains, highlighting the tool’s potential usefulness in guiding decisions about study design, but also revealing a number of challenges in applying it and interpreting the results.
Study authors Johnson and Neta will be discussing their findings during the NIH Collaboratory’s Grand Rounds on Friday, January 22, 2016 (an archived version of the presentation will be available the following week).
Johnson KE, Neta G, Dember LM, Coronado GD, Suls J, Chambers DA, Rundell S, Smith DH, Liu B, Taplin S, Stoney CM, Farrell MM, Glasgow RE. Use of PRECIS ratings in the National Institutes of Health (NIH) Health Care Systems Research Collaboratory. Trials. 2016;17(1):32. doi: 10.1186/s13063-016-1158-y. PMID: 26772801. PMCID: PMC4715340.
You can read more about the NIH Collaboratory PCTs featured as part of this project at the following links:ABATE (Active Bathing to Eliminate Infection)
LIRE (A pragmatic trial of Lumbar Image Reporting with Epidemiology)
PPACT (Collaborative Care for Chronic Pain in Primary Care)
STOP-CRC (Strategies & Opportunities to Stop Colon Cancer in Priority Populations)
TIME (Time to Reduce Mortality in End-Stage Renal Disease)
Additional Resources
An introductory slide set on PCTs (by study author Karin Johnson) is available from the Living Textbook:
Introduction to Pragmatic Clinical Trials
The University of Colorado Denver - Anschutz Medical Campus publishes an electronic textbook on pragmatic trials:
Pragmatic Trials: A workshop Handbook
The 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.
A new report (PDF) containing recommendations for the creation of a national registry system for evaluating and monitoring medical devices has been released for public comment today. The report, a joint project of the Medical Device Registry Task Force and the Medical Device Epidemiology Network (MDEpiNet), is available on boh the US Food and Drug Administration (FDA) website and on the MDEpiNet website.
The report reflects the results of a year-long effort, prompted by the FDA’s Center for Devices and Radiological Health (CDER), that is focused on fostering a national system for monitoring the use of medical devices in the “real-world” setting of patient care, once the devices have been approved for the market (known as “postmarket surveillance”).
The term “medical devices” encompasses a wide range of technologies, including implantable pacemakers, cardiovascular stents, robotic surgical devices, and artificial joint replacements, among many others. At present, information about the use of these devices in routine care settings, including safety issues reported by doctors and patients, is collected in a variety of registries and health record systems. A networked national system, such as the one described in the task force report, would be able to unite and build upon both existing and novel data resources, thereby improving safety monitoring and accelerating the development of new devices:
“Task Force recommendations for [Coordinated Registry Network] CRN architecture, and thus for the National System, center on leveraging existing, self sustaining electronic resources, such as device registries, electronic health records, administrative data and even social media and personal mobile device sources.”
The Task Force Report offers recommendation in several key areas, including:
Establishing a national dialog about medical device evaluation that includes all stakeholders;
Leveraging existing efforts in the arena of device registries and electronic data systems;
Describing the desired characteristics of a national Coordinated Registry Network (CRN) for medical devices;
Outlining priorities for developing and refining medical devices in multiple therapeutic areas;
Identifying and improving methods for analyzing data on medical devices; and
Addressing network governance and issues related to patient privacy and informed consent.
Each of these key areas also features suggested pilot projects designed to inform ongoing efforts.
A related perspective article summarizing the National Registry System project has also been published online in the Journal of the American Medical Association.
The National Patient-Centered Clinical Research Network (PCORnet) has recently made a draft protocol for its first randomized clinical trial available for stakeholder review. Researchers, clinicians, patients and the public are all invited to read the current draft of the study protocol and provide comments and feedback.
The ADAPTABLE Study (PDF), which will investigate whether lower- or higher-dose aspirin is better for preventing heart attack and stroke in patients at risk for heart disease, is PCORnet’s first randomized pragmatic clinical trial. Designed to leverage PCORnet’s Clinical Data Research Networks (CDRNs) and Patient-Powered Research Networks (PPRNs), the trial will serve as twofold purpose: answering a clinical question of direct importance for patients, families, and healthcare providers, and serving as a demonstration of PCORnet’s capabilities in conducting clinical research on a national scale.
Links to the proposed study protocol, a survey tool for capturing feedback, and other information about ADAPTABLE Study, including press releases, fact sheets, and infographics, are available at the link below:
In January of 2015, the NIH HCS Collaboratory’s Patient-Reported Outcomes (PRO) Core Group convened a 2-day workshop in Baltimore devoted to identifying barriers and possible solutions to the use of NIH-supported PRO tools in comparative-effectiveness research (CER).
Findings from the meeting, which include case study presentations and reflections from multiple stakeholders representing the research, clinical, and patient communities, were distilled into a summary document available from the NIH Collaboratory Knowledge Repository at the link below:
As part of a project that examined the degree to which sponsors of clinical research are complying with federal requirements for the reporting of clinical trial results, the Clinical Trials Transformation Initiative (CTTI) and the authors of the study are making the primary dataset used in the analysis available to the public. The full analysis dataset, study variables, and data definitions are available as Excel worksheets from the CTTI website and on the Living Textbook’s Tools for Research page.
A persistent problem facing the clinical research enterprise is the difficulty of negotiating the terms of contracts under which clinical trials will be performed at individual clinical research sites. For many research centers, the process is complex and protracted, and can often contribute to substantial delay in study start-up.
However, the Clinical and Translational Science Award (CTSA) Master Contracts Working Group has recently developed a possible solution—the Accelerated Clinical Trial Agreement, or ACTA. The ACTA provides a standardized template for contracts between site investigators and study sponsors, one with the potential to expedite contracting and make the start-up process for clinical trials more efficient.
