May 16, 2019: NIH Collaboratory Investigators Author Recommendations for Responding to Guideline or Policy Changes That Affect Ongoing Pragmatic Trials

A new perspective article by NIH Collaboratory investigators describes the unique, unexpected challenges researchers face when clinical practice guidelines and policies change during the conduct of a pragmatic clinical trial (PCT). The article was published online this week in Clinical Trials.

The NIH Collaboratory Demonstration Projects are PCTs that test interventions to address urgent public health problems. They involve hundreds to thousands of participants and generally include usual care as a control arm. During the course of these years-long trials, clinical practice guidelines and policies changed due to new evidence from observational studies, small trials, and shifting expert opinion. Such changes can have profound effects on usual care and, therefore, threaten the ability of the PCTs to address the questions they were designed to answer. Investigators must strike a balance between the primary ethical obligation to protect patients by adhering to new best-practice guidelines and policy and the secondary, yet crucial, obligation to develop high-quality evidence to improve care.

“PCTs are an important means of producing high-quality evidence needed to better inform clinical practice. However, when guidelines or reimbursement policies change during the conduct of a PCT, the ethical obligation to gather information to develop evidence-based practices may conflict with the primary ethical obligation to participants.” — Curtis et al, Clinical Trials, 2019

Based on their aggregate experience with the NIH Collaboratory, the authors provide broad recommendations and strategies for overcoming these challenges, including protecting the well-being of patients; involving stakeholders, health system leaders, and the entity charged with data and safety monitoring; and actively monitoring changes and site-level responses to them. If changes to the standard of care are merited, investigators should provide equal opportunity and support for the recommended changes. Finally, during the design phase, investigators should communicate with the entities charged with creating guidelines to see what is needed and to anticipate possible future changes.

“The ability to appropriately address the tension between modifications to clinical guidelines and the need to generate quality evidence to support those guidelines is a crucial consideration for the fulfilment of a learning health system.” — Curtis et al, Clinical Trials, 2019

NIH Workshop: Design & Analysis of Embedded Pragmatic Clinical Trials

The NIH Health Care Systems Research Collaboratory is hosting a one-day workshop on the Design & Analysis of Embedded Pragmatic Clinical Trials (ePCTs) on May 2, 2019, in the Lister Hill Auditorium on the NIH Campus.

The workshop will include a series of moderated discussions that focus on issues of measuring trial outcomes from available data sources, potential randomization strategies, specific ePCT design considerations, and unique challenges associated with ePCTs. Panel discussions will utilize case examples from the Collaboratory repertoire and beyond to illustrate how clinical investigators and biostatisticians work to address research questions posed by specific trials.

The Workshop Website provides information on meeting logistics, agenda, and registration. There is also an option to attend the workshop remotely via the NIH Videoconference Center, and those details are also available at the Workshop Website.

April 19, 2019: Trauma Survivors Outcomes & Support (TSOS) Pragmatic Trial: Revisiting Effectiveness & Implementation Aims (Doug Zatzick, MD)

Speaker

Doug Zatzick, MD
Professor of Psychiatry
Harborview Medical Center
University of Washington School of Medicine

Topic

Trauma Survivors Outcomes & Support (TSOS) Pragmatic Trial: Revisiting Effectiveness & Implementation Aims

Keywords

Trauma outcomes; Demonstration Project; Hybrid study design; Implementation science; Pragmatic clinical trial; Cluster randomization; Stepped-wedge design; Posttraumatic stress disorder; PRECIS-2; Mental health intervention

Key Points

  • The TSOS Demonstration Project is a cluster-randomized, stepped-wedge trial conducted at 25 U.S. trauma centers. The intervention involves an electronic health record PTSD screen and a baseline PTSD and comorbidity assessment. TSOS is turned on at each site across 4 “waves.”
  • During the course of this hybrid effectiveness-implementation trial, two domains on PRECIS-2 (Pragmatic-Explanatory Continuum Indicator Summary) were scored as more pragmatic and one domain as more explanatory than at the outset of the study.
  • The study team developed a methodology for assessing TSOS implementation aims. Called RAPICE (Rapid Assessment Procedure Informed Clinical Ethnography), the method yielded findings around recurrent intervention and research staff turnover across sites; observations that some patients do not engage in the intervention; and ways to inform a priori secondary hypotheses that suggest per-protocol modifications to the original intention-to-treat analyses.
  • TSOS will present results at the 2020 summit of the American College of Surgeons with the potential to integrate findings into the College’s regulatory and verification processes.

Discussion Themes

Regarding the need to collect outcome data, there may be an important distinction between two aspects of “pragmatic.” That is, while collecting outcome data makes a trial more expensive (one aspect of pragmatic), it doesn’t necessarily affect relevance or generalizability (another, more important, aspect of pragmatic).

Might there be studies which, by design, are not aiming to be on the outer [more pragmatic] spokes of the PRECIS-2 wheel?

Read more about the TSOS Demonstration Project.

Tags

#pctGR, @Collaboratory1, @PRECIS_2

April 5, 2019: The ENGAGES Pragmatic Trial and the Power of Negative Thinking (Michael S. Avidan, MBBCh)

Speaker

Michael S. Avidan, MBBCh
Dr. Seymour and Rose T. Brown Professor of Anesthesiology
Chief, Division of Clinical and Translational Research
School of Medicine, Department of Anesthesiology
Washington University in St. Louis

Topic

The ENGAGES Pragmatic Trial and the Power of Negative Thinking

Keywords

Pragmatic clinical trial; Surgery; Electroencephalography; EEG-guided anesthesia; Postoperative delirium; Older patients; Patient-centered outcomes; ENGAGES

Key Points

  • The ENGAGES pragmatic trial evaluated whether electroencephalogram-guided anesthetic administration decreases postoperative delirium incidence in older patients undergoing major surgery.
  • Delirium is a disturbance in consciousness or change in cognition for a short period of time as a consequence of a medical illness. 25% to 50% of older adults experience delirium after major surgery, and the number is even higher for ICU patients.
  • The ENGAGES trial found that, among older adults undergoing major surgery, EEG-guided anesthetic administration, compared with usual care, did not decrease the incidence of postoperative delirium.

Discussion Themes

Aside from the intensity of patient follow-up and the expertise needed to deliver the EEG-guided protocol, the ENGAGES study fulfilled the criteria for a pragmatic clinical trial as shown in PRECIS-2 ratings.

Clinicians participating in ENGAGES were not researchers but carried out the intervention on the ground. They understood the appeal of it and found it easy to implement.

With respect to study findings, instead of referring to “negative” or “null” findings, why not say, “this is what we found and these are interesting findings.”

Learn more about the results of the ENGAGES trial in JAMA (Feb 2019).

Tags

#delirium, #pctGR, @Collaboratory1, @WUSTL_med

April 9, 2019: EMBED Awarded Continuation From Planning to Implementation Phase

The investigators of EMBED, an NIH Collaboratory Demonstration Project, have received approval to move from the planning phase to the implementation phase of their study. Congratulations to Dr. Ted Melnick, Dr. Gail D’Onofrio, and the EMBED study team for their excellent work!

“The opioid crisis is taking a devastating toll on Americans, their families, and their communities. The EMBED project leverages the urgency of our nation’s opioid crisis to bring together leaders in human-centered design, clinical informatics, data coordination, emergency medicine, and addiction medicine to provide an integrated, user-friendly solution to emergency clinicians caring for people with opioid addiction.”   —Dr. Edward Melnick, Co-PI of EMBED

EMBED (Pragmatic Trial of User-Centered Clinical Decision Support to Implement Emergency Department-Initiated Buprenorphine for Opioid Use Disorder) is designed to evaluate the effect of computerized clinical decision support on rates of emergency department-initiated buprenorphine/naloxone (BUP), which is a well-established outpatient treatment for people with opioid use disorder. BUP can only be prescribed by appropriately trained physicians. Although patients with opioid use disorder often seek medical care in emergency departments, the practice of initiating BUP in the emergency department is not common.

“Initiating buprenorphine in the emergency department has the potential to improve and save so many lives, but currently adoption rates are close to 0%. We believe that the EMBED intervention will be a crucial part of getting this evidence-based practice into routine emergency care.”   —Dr. Edward Melnick, Co-PI of EMBED

NIH Collaboratory Demonstration Projects begin with a 1-year, milestone-driven planning phase. Projects become eligible to move to the implementation phase after an administrative review of progress toward scientific milestones and feasibility requirements.

In the planning phase, the EMBED study team developed the clinician decision support tools intended to facilitate the management of people with untreated opioid use disorder who seek care in emergency departments. In the next phase, the team will implement the trial and test the effect of the clinical decision support tool compared to usual care on outcomes in patients with opioid use disorder who seek care in emergency departments.

EMBED was supported within the NIH Collaboratory by a cooperative agreement from the National Institute on Drug Abuse. The study also received logistical and technical support from the NIH Collaboratory Coordinating Center through a cooperative agreement from the Office of Strategic Coordination within the Office of the NIH Director.

 

April 1, 2019: Pre-Conference Seminar on Essentials of ePCTs Offered at AcademyHealth’s June 2019 Annual Research Meeting in D.C.

The NIH Collaboratory is partnering with AcademyHealth to offer a full-day pre-conference seminar at the 2019 Annual Research Meeting in Washington, D.C. Essentials of Embedded Pragmatic Clinical Trials will provide an introduction to the investigative opportunities for embedded health systems research, along with strategies for conducting clinical trials that provide real-world evidence necessary to inform both practice and policy. Firsthand ePCT experiences and case studies from the NIH Collaboratory will support and illustrate the topics presented. Speakers will include program officers and senior staff from NIH Institutes and Centers and senior investigators from the Collaboratory Demonstration Projects and Coordinating Center.

Learning objectives include:

  • To clarify the definition of ePCTs and explain their utility.
  • To introduce attendees to the unique characteristics and challenges of designing, conducting, and implementing ePCTs within diverse health care systems.
  • To increase the capacity of health services researchers to address important clinical questions with ePCTs.
Seminar Details & Registration
Monday, June 1, 2019
8 am to 5 pm
Walter E. Washington Convention Center
Washington, D.C.

March 13, 2019: PROVEN Publishes Study of Nursing Home Characteristics Associated With Implementation of an Advance Care Planning Video Intervention

The Collaboratory Demonstration Project Pragmatic Trial of Video Education in Nursing Homes (PROVEN) is testing the effectiveness of a novel advance care planning (ACP) video education program in 360 nursing homes within 2 large nursing home healthcare systems. The investigators of PROVEN recently published a study that examines the characteristics of nursing homes associated with implementation of the video. They found that lower quality nursing homes (rated 1 star) had lower offer rates than higher quality nursing homes, suggesting that ongoing support might be necessary in these settings, as well as engagement with a local champion.

ACP is a process by which individuals define their future goals and preferences for medical treatment at the end of life and discuss these goals with their family and healthcare providers. ACP is especially important for nursing home residents, who often receive unnecessary care and experience burdensome transitions at the end of life. The ACP intervention in PROVEN is delivered by an onsite champion at the facility—usually a social worker with structured training in how and when to offer and show the ACP videos to residents and families.

 “These results have implications for future pragmatic trials in the NH [nursing home] setting because ongoing engagement between research and NH staff appears crucial for successful integration of interventions into routine clinical practice. Future research is needed to understand how to best engage NHs in implementation and encourage communication between NHs to share pragmatic strategies for improving clinical practice without the support of research staff.”

– Loomer et al. Journal of the American Medical Directors Association

March 6, 2018: Results of the Active Bathing to Eliminate (ABATE) Infection Trial Published in The Lancet

The Active Bathing to Eliminate (ABATE) Infection trial compared routine bathing to decolonization with universal chlorhexidine and targeted nasal mupirocin in non-critical-care units. Similar interventions have been found to reduce multidrug-resistant pathogens and bloodstream infections in intensive care units (ICUs), and this was the first large-scale trial in non-critical-care units. The primary outcome was methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant enterococcus (VRE) clinical cultures attributed to participating units.

“We found that universal decolonization did not reduce infection in the overall population, but in post-hoc analyses of patients with medical devices the regimen was associated with significant reductions in all-cause bloodstream infections and MRSA or VRE clinical cultures.” —Huang et al. The Lancet 2019

The ABATE Infection trial was a large-scale pragmatic trial involving approximately189,000 patients in the baseline period and 340,000 patients in the intervention period across 194 non-critical-care units in 53 hospitals. The trial was one of the first NIH Collaboratory Demonstration Projects, and in keeping with the Collaboratory’s mission, the investigators have helped expand the knowledge base about the design, conduct, and dissemination of pragmatic clinical trials.

March 5, 2019: New Living Textbook Section on Using Death as an Endpoint

Using death as an endpoint in pragmatic clinical trials is challenging because there are no standardized processes for ascertaining patient deaths in the United States. If a patient dies outside of a clinical care system, ascertaining if and how a death has occurred is considerably complicated. There are multiple sources of vital statistics data, each with different amounts of lag time, linking approaches, costs, and specificity of information. For example, some sources include cause of death while others include only fact of death; some have a lag time of a few months and some may take over a year; some charge by the individual file and some have an annual subscription fee.

This section of the Living Textbook describes different death data sources, how to obtain information from them, and the pros and cons of each.

“Death identification and adjudication may be more complicated with pragmatic clinical trials (PCTs) that rely on data collected from the patient’s electronic health record (EHR), medical claims, self-report, or medical devices.” —Eisenstein E, et al. Choosing and Specifying Endpoints and Outcomes: Using Death as an Endpoint. In: Rethinking Clinical Trials: A Living Textbook of Pragmatic Clinical Trials.

The sources of data described in this section include the Death Master File, the Medicare Master Beneficiary Summary File, state vital statistics, the Fact of Death File, the National Death Index, and call centers. The section also presents a case study to illustrate a hybrid death identification and verification approach used in the ToRsemide compArisoN with furoSemide FOR Management of Heart Failure (TRANSFORM-HF) PCT (ClinicalTrials.gov Identifier: NCT03296813).

 

March 1, 2019: Approaches to Patient Follow-Up for Clinical Trials: What’s the Right Choice for Your Study? (Keith Marsolo, PhD)

Speaker

Keith Marsolo, PhD
Department of Population Health Sciences
Duke Clinical Research Institute
Duke University School of Medicine

Topic

Approaches to Patient Follow-Up for Clinical Trials: What’s the Right Choice for Your Study?

Keywords

Pragmatic clinical trial; Real-world data; Distributed research network; Electronic health records; EHR; Health data sources; Data standardization; Common data model; Fast Healthcare Interoperability Resources (FHIR); Application programming interface (API)

Key Points

  • Different sites have different capabilities and levels of sophistication around data. Clinical trial investigators should think from the beginning about the questions they want to answer and how much data is needed.
  • From different sources, such as the EHR, claims, or participant, data can be procured and provided in different ways, either by the patient, staff or clinician, or through IT and data experts.
  • PCTs with many sites may require a “patchwork quilt” of approaches for patient follow-up depending on the needs of the trial. Clinician-generated reports, direct from patients, and solutions involving application programming interfaces (APIs) are all good options for data exchange.

Discussion Themes

How do we think through the options for getting patient data where some sites may not be in the distributed research network or use a common data model?

Fast Healthcare Interoperability Resources (FHIR) is a draft standard describing data formats and elements and an application programming interface (API) for exchanging electronic health records. The FHIR interface requests data as an object, and for each defined domain it specifies allowable values and variables and predefines the information that you get out of the system.

Until data are collected/generated using the same standards/formats as the API, there will still be a need to understand the EHR-to-interface mapping.

For more information on using health data in embedded pragmatic clinical trials, visit the NIH Collaboratory’s EHR Core webpage.

Tags

#CommonDataModel, #RealWorldData, #FHIR, #pctGR, @Collaboratory1