October 11, 2019: Objecting to Experiments that Compare Two Unobjectionable Policies or Treatments: Implications for Comparative Effectiveness and Other Pragmatic Clinical Trials (Michelle Meyer, PhD, JD)

Speaker

Michelle N. Meyer, PhD, JD
Assistant Professor & Associate Director, Research Ethics
Center for Translational Bioethics & Health Care Policy
Faculty Co-Director, Behavioral Insights Team
Steele Institute for Health Innovation, Geisinger

Topic

Objecting to Experiments that Compare Two Unobjectionable Policies or Treatments: Implications for Comparative Effectiveness and Other Pragmatic Clinical Trials

Keywords

A vs B trials; Comparative effectiveness research; Clinical equipoise; Randomization; Learning health system

Key Points

  • Healthcare delivery systems often have an ethical obligation to experiment in order to determine the effects of their policies and treatments on stakeholders. A/B experiments conducted within health systems are intended to increase quality and safety, decrease waste or lower costs, and reduce inequity and injustice.
  • The “A/B effect” is the approval of untested policies or treatments (A or B) being universally implemented but disapproval of randomized experiments (A/B tests) to determine which of those policies or treatments is superior.
  • Experimentation aversion may be an important barrier to evidence-based practice.

Discussion Themes

Do you think the objection to random assignment is related to a sense that it is not “random?”

A potential solution to the “A/B effect” is to let patients be partners in improving healthcare by explaining that “we don’t know if A or B is better. Would you be willing to help us find out?”

Read Dr. Meyer and colleagues’ open access article in the journal Proceedings of the National Academy of Sciences (May 2019): Objecting to experiments that compare two unobjectionable policies or treatments.

Tags
#pctGR, @Collaboratory1

September 20, 2019: Designing & Testing the Future of Home-based Cervical Cancer Screening: Results from a Collaborative Academic-Embedded Delivery System Pragmatic Randomized Trial (Rachel L. Winer, PhD; Diana S.M. Buist, PhD, MPH)

Speakers

Rachel L. Winer, PhD
University of Washington
School of Public Health
Department of Epidemiology

Diana S.M. Buist, PhD, MPH
Kaiser Permanente Washington Health Research Institute

Topic

Designing & Testing the Future of Home-based Cervical Cancer Screening: Results from a Collaborative Academic-Embedded Delivery System Pragmatic Randomized Trial

Keywords

Embedded pragmatic clinical trial; Cervical cancer screening; Human papilloma virus

Key Points

  • The aim of the Home-Based Options to Make Screening Easier (HOME) pragmatic randomized trial was to compare the effectiveness of 2 approaches to increasing cervical cancer screening among women 30-64 years of age who are overdue for cervical cancer screening.
  • Challenges of embedded pragmatic trials reported by the study team include:
    • Discussions with lab, primary care, OB/GYN, and prevention and outreach teams
    • Negotiation about the target population
    • Aligning with evolving clinical guidelines
    • Engaging multiple clinical champions
    • Extensive back and forth with IRB for approval
  • The study team also conducted semi-structured interviews to understand women’s attitudes, emotional responses, and informational needs after receiving a positive kit result and completing recommended follow up.

Discussion Themes

Were you able to assess the impact of this intervention on the clinic staff?

To help move the field forward, there is a need for more publications and more education of peer reviewers and funders about the challenges of conducting embedded pragmatic trials.

Read more about the HOME pragmatic trial design and suggestions for how to improve the promise of embedded pragmatic trials.

Tags

#pctGR, @Collaboratory1

September 13, 2019: HiLo Awarded Continuation From Planning to Implementation Phase

The investigators of HiLo, an NIH Collaboratory Demonstration Project, have received approval to move from the planning phase to the implementation phase of their study. Congratulations to Dr. Myles Wolf and the HiLo study team for their excellent work!

HiLo (Pragmatic Trial of Higher vs. Lower Serum Phosphate Targets in Patients Undergoing Hemodialysis) is designed to answer the question of what is the optimal level of serum phosphate for patients with end-stage renal disease (ESRD) who are undergoing hemodialysis. In an effort to improve clinical outcomes, current practice guidelines advocate aggressive treatment of high blood phosphate to near normal levels using dietary phosphate binders and restrictive diets. Yet, the optimal phosphate target remains unknown, and potential harms of aggressive treatment have not been definitively identified. HiLo is the first formal clinical research study to evaluate this important question. The study team is planning the first wave of site activations with the goal of beginning enrollment at 10 dialysis centers in the Raleigh-Durham area in October or November.

We recently asked Dr. Wolf to reflect on the transition of the HiLo trial.

Were there any surprises during the study’s planning phase?

How much work was required to plan a large pragmatic trial! Fortunately, we have a superb team of investigators and study staff who are deeply invested in the trial, deep expertise at the Duke Clinical Research Institute, full engagement of our partners at DaVita and the University of Utah, invaluable insight from our Patient Ambassadors from the American Association of Kidney Patients, and unwavering support from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the NIH Collaboratory.

What is an example of a challenge that you were able to overcome with the help of a Core group?

The Ethics and Regulatory Core helped us work through unique challenges related to obtaining individual-level informed consent in a cluster-randomized trial. The Biostatistics and Study Design Core and a number of outside statistical consultants helped us identify a novel solution for designing and analyzing a primary outcome of the trial that best aligns with the study’s clinical goal.

“We hope that the experience we gained from HiLo related to application of novel methods for pragmatic trials will stimulate further innovation and enhance the design of future studies in our field, ultimately for the benefit of kidney patients.” – Dr. Myles Wolf, PI of HiLo

What other key challenges have you faced?

We learned from the Ambassadors on our Patients Advisory Group about how important it will be to convince dialysis facility staff and patients that it is justified and important for the study to reevaluate what has been dogma in ESRD treatment: that serum phosphate must be lowered aggressively. We have had to grapple with how to deploy an electronic process to obtain informed consent remotely—a first in U.S. dialysis studies—given that we will not have on-site study coordinators in the participating dialysis facilities. We also had to develop, refine, and defend our use of a newer statistical approach to HiLo’s primary hierarchical composite outcome of all-cause mortality and all-cause hospitalizations. The approach, which is gaining traction in other areas, has not been used in large-scale trials in nephrology. While the process of preparing for this trial was long and required substantial hard work from a large team of investigators and study staff, we hope that the experience we gained from HiLo related to application of novel methods for pragmatic trials will stimulate further innovation and enhance the design of future studies in our field, ultimately for the benefit of kidney patients.

What words of advice do you have for investigators conducting their first embedded PCT?

Get to know the people—patients and professionals—who need to be invested and will be affected by your study and its outcomes. Understand their interests and concerns even if it goes against what you think you know. These early conversations will help identify hurdles at a time when they can be readily addressed and the study enhanced. Be patient and be prepared to work, and work some more. And ask for more money … pragmatic plus more resources is still pragmatic!

Additional details about the study are on the HiLo website.

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. Throughout the process, the project team interacts with the Core Working Groups and investigators from the other Demonstration Projects.

HiLo is supported within the NIH Collaboratory by a cooperative agreement from the NIDDK and receives logistical and technical support from the NIH Collaboratory Coordinating Center. Read more about HiLo in the Living Textbook, and learn more about the NIH Collaboratory Demonstration Projects.

July 3, 2019: New Article Describes the Public’s Beliefs Regarding Responsibility to Participate in Research

Findings from a new article suggest that the majority of patients do not feel a personal responsibility to participate in clinical research. In the article, Kevin Weinfurt, Li Lin, and Jeremy Sugarman report the results of a national survey of nearly 3000 people regarding their attitudes towards research responsibilities as well as their trust in doctors, healthcare systems, and medical research. Ethical frameworks for learning health systems have suggested that patients have a responsibility to contribute to learning activities, including research. The findings from this survey suggest that most patients in the U.S. do not currently endorse such a responsibility.

“These data provide a useful snapshot of the public’s views toward the obligation to participate in research. It is unclear how, if at all, these views will shift with increased efforts to create mature learning health systems. And if such views do not shift, it is uncertain what that would mean for the success of learning health systems.” —Kevin Weinfurt, PhD

Read the full article: Public Views Regarding the Responsibility of Patients, Clinicians, and Institutions to Participate in Research in the U.S.

For more on alternate approaches to consent, see the Living Textbook Chapter on Consent, Disclosure, and Non-Disclosure

June 21, 2019: A Polypill Strategy for Cardiovascular Prevention in Underserved Populations–Can We Bridge the Gap? (Daniel Munoz, MD, MPA, Thomas Wang, MD)

Speakers

Daniel Muñoz, MD, MPA
Assistant Professor of Medicine
Division of Cardiology
Vanderbilt University Medical Center

Thomas J. Wang, MD
Professor of Medicine
Gottlieb C. Friesinger II Chair in Cardiovascular Medicine
Director, Division of Cardiovascular Medicine
Vanderbilt University Medical Center
Physician-in-Chief, Vanderbilt Heart & Vascular Institute

Topic

A Polypill Strategy for Cardiovascular Prevention in Underserved Populations–Can We Bridge the Gap?

Keywords

Cardiovascular health; Prevention; Underserved populations; Health disparities; Southern Cohort Community Study (SCCS); Health outcomes

Key Points

  • Despite therapeutic advances in preventing cardiovascular disease, risk factors (blood pressure, cholesterol) and disease burden remain high in vulnerable populations.
  • Drivers of cardiovascular health disparities include inadequate access to healthcare, economic barriers, lifestyle and cultural barriers, and low adherence to medication.
  • A “polypill” strategy for prevention involves a once-daily, fixed-dose combination of 4 to 5 medications. The Southern Cohort Community Polypill Trial tested whether use of a polypill would control cardiovascular risk factors better than usual care in an at-risk U.S. primary prevention subpopulation.

Discussion Themes

The “prevention paradox” is that most people who get heart disease are at low predicted risk.

Which is the better approach to preventing cardiovascular disease—a high-risk, personalized approach or a pragmatic, population approach?

A federally qualified health clinic network can serve as an effective platform to study and address cardiovascular disease health disparities.

Read more about the SCCS Polypill Pilot Trial in a recent publication, Polypill for Cardiovascular Disease Prevention in an Underserved Population.

Tags

#pctGR, @Collaboratory1

June 13, 2019: Experience With Pragmatic Clinical Trials Gains Momentum

At the NIH Collaboratory Steering Committee Meeting in May 2019, participants shared their perspectives on the evolving landscape of embedded pragmatic clinical trials (ePCTs). Three initiatives were presented: the Patient-Centered Outcomes Research Institute (PCORI), the NIH-DoD-VA Pain Management Collaboratory, and the HEAL (Helping to End Addiction Long-term) Initiative. Although many challenges remain, the conduct of ePCTs is gaining momentum, and the synergy between the initiatives, along with the fellowship they engender, will continue to help pave the way for more embedded pragmatic research in the future.

Dr. Ann Trontell, Associate Director of Clinical Effectiveness and Decision Science at PCORI, shared PCORI’s experience with pragmatic clinical studies. Since 2014, PCORI has awarded $494 million dollars for 43 pragmatic studies that range in size from 425 to 100,000 participants (median, approximately 1700). The studies include 2 observational, 27 individually randomized, and 14 cluster randomized trials in a wide range of therapeutic areas.

Dr. Trontell urged those developing proposals for pragmatic trials to make them fit for purpose, as opposed to emphasizing pragmatism, a theme echoed in the Developing a Compelling Grant Application chapter of the Living Textbook.

 

 

 

 

Dr. Robert Kerns, a director of the NIH-DoD-VA Pain Management Collaboratory, shared progress with pragmatic trials designed to evaluate whether evidence-based nonpharmacological approaches are effective for pain management among US military personnel and veterans.

Modeled after the NIH Collaboratory, the Pain Management Collaboratory is supporting 11 projects through a 2-year planning phase and a 2- to 4-year implementation phase. Subject matter experts at the Pain Management Collaboratory Coordinating Center (PMC3) support the projects by sharing tools, best practices, and resources.

 

Dr. Wendy Weber, Program Officer for the NIH Collaboratory Coordinating Center, introduced the HEAL initiative, which is designed to enhance pain management and improve prevention and treatment strategies for opioid misuse and addiction. The goal of the initiative is to provide scientific solutions to the opioid crisis. It includes a set of large-scale pragmatic trials that will receive logistical and technical support from the NIH Collaboratory Coordinating Center.

 

While experience with ePCTs is growing, many distinct challenges remain. As the conduct of ePCTs gains momentum, there is a rich opportunity to use collective experiences to refine best practices to real-world evidence generation and help solve urgent public health problems.

May 31, 2019: Adapting Clinical Trial Design to Meet the Needs of Learning Health Systems (Harriette Van Spall, MD, MPH)

Speaker

Harriette G.C. Van Spall, MD, MPH, FRCPC
Associate Professor of Medicine
Department of Medicine, Division of Cardiology
Department of Health Research Methods, Evidence, and Impact
McMaster University
Population Health Research Institute

Topic

Adapting Clinical Trial Design to Meet the Needs of Learning Health Systems

Keywords

Learning health system; Pragmatic clinical trial; Patient-Centered Care Transitions in Heart Failure (PACT-HF); Heart failure; Stepped-wedge cluster trial

Key Points

  • Characteristics of a learning health system include:
    • Possessing a culture of knowledge and quality improvement
    • Encouraging research innovation by embedding research into clinical practice and generating knowledge at the point of care
    • Harnessing data from electronic health records and claims/administrative databases
    • Fostering trust between research and clinical teams
    • Engaging patients, clinicians, and key stakeholders
  • The Patient-Centered Care Transitions in Heart Failure (PACT-HF) trial evaluated the effectiveness of a group of transitional care services in patients hospitalized for HF within a publicly funded healthcare system.
  • Challenges of a learning health system include integrating care, intervention, and communications across silos; streamlining workflow; preventing “contamination” of usual care; and the limited interoperability of EHRs and slow updates to claims/administrative datasets.

Discussion Themes

Efficacy in explanatory randomized clinical trials (RCTs) does not equate to effectiveness in real-world settings.

Decisions about implementation of an intervention are not made “live”; you must wait until the study has ended, all the data are available for analysis, and analysis is complete before you can inform decision-maker partners about the risks and benefits of the intervention.

Read more about the PACT-HF study and results in JAMA Network (Van Spall et al. 2019)

Tags

#pctGR, @Collaboratory1

April 26, 2019: The VERITAS Trial: Virtual Exercise Rehabilitation at the Intersection of Evidence, Implementation, and Policy (Janet Prvu Bettger, ScD)

Speaker

Janet Prvu Bettger, ScD, FAHA
Associate Professor
Duke Department of Orthopaedic Surgery
Duke Clinical Research Institute

Topic

The VERITAS Trial: Virtual Exercise Rehabilitation at the Intersection of Evidence, Implementation, and Policy

Keywords

Rehabilitation; Virtual physical therapy; Patient outcomes; Physical therapy; Orthopaedic surgery; Total knee replacement; Digital technology; Telehealth

Key Points

  • The VERITAS trial evaluated the effects of physical therapy–supported virtual exercise compared with traditional home- or clinic-based physical therapy after total knee replacement. Outcome measures included 90-day health service use costs; patient-centered outcomes; and differential improvement from 6 weeks to 3 months.
  • The Center for Connected Health Policy found that while most states currently have established telehealth policies for primary care providers, these often do not include physical or occupational therapists.
  • Tele-rehabilitation facilitates communication between the patient and physical therapist in real time. The VERA™ technology provides a virtual physical therapist assistant for patients and clinicians, offering a digital interface that includes patient education, longitudinal functional assessments, telehealth video conferencing, personalized exercises, and remote monitoring of patient progress.

Discussion Themes

Study results support effectiveness and safety hypotheses: that tele-rehabilitation is noninferior to traditional physical therapy with respect to range of motion, walking speed, pain, or rehospitalization. However, it was not shown that the intervention is noninferior with respect to falls after hospital discharge.

Because virtual physical therapy interventions can save total costs, prevent readmissions, and improve mobility, it will be important to expand access to tele-rehabilitation and to advance policies that include physical therapists.

Read more about the VERITAS project and at ClinicalTrials.gov.

Tags

#telehealth, #pctGR, @Collaboratory1

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

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.