Pragmatic clinical trial

April 18, 2024: New Living Textbook Chapter Articulates How Investigators Navigated Unexpected Challenges During Pragmatic Clinical Trials

Posted on by Karen Staman

During the course of the years-long pragmatic clinical trials supported by the NIH Pragmatic Trials Collaboratory, many unanticipated challenges have occurred, some of which have had profound effects on usual care, trial implementation, data systems, and staff. These unanticipated changes threatened the ability of the trials to address the questions they were designed to answer. A new chapter of the Living Textbook—Navigating the Unknown—describes these challenges and the responses of the study teams.

The chapter describes 3 general categories of challenges, each meriting a different response:

  1. If the challenge is a local or temporary issue (for example, a pandemic temporarily shuts down in-person care, or a partnering health system dissolves or is purchased), but the question is still relevant or important and the trial is still feasible, then a workaround may solve the problem.
  2. If the trial is no longer feasible for some reason (for example, the recruitment process is not feasible, or the intervention cannot be delivered as planned), and the question is still relevant, it is necessary to make significant changes to the protocol.
  3. If the question is no longer relevant or important (for example, new evidence or policy changes make the question no longer relevant), the trial should not continue. For this challenge, it may necessary either to stop the trial or to make fundamental changes to address a different question (since the original question is no longer relevant).

The chapter describes local or temporary challenges some of the study teams faced, such as the COVID-19 pandemic, health system mergers, and changes to the electronic health record (EHR). In these cases, the research questions were still relevant and important and the trial designs were still feasible, so workarounds were created to solve the problems.

  • Section 2: Study teams responded to staff turnover, leadership changes, and health system acquisitions and mergers.
  • Section 3: Rapid technology change created unexpected consequences, such as EHR updates causing system changes that affected intervention delivery, and sites switching EHRs systems creating complexities during the trial.
  • Section 4: COVID-19 had significant impacts on trial activities.

Section 5 of the new chapter addresses barriers that resulted from aspects of the protocol that could have impacted recruitment, retention, or implementation in a way that imperiled the ability of trials to answer the question posed by a research study. In these scenarios, researchers found it appropriate to change the protocol or research question—to pivot—in order to glean meaningful, actionable evidence.

Sections 6 and 7 describe challenges that can fall into either category 1 or 2, and investigators had to decide how to respond in real time.

  • Section 6: Clinical practice guidelines and policies changed due to new evidence from observational studies, small trials, and shifting expert opinion, and therefore, usual care changed.
  • Section 7: Quality improvement initiatives were launched to address similar problems, threatening the ability to discern differences between arms of the trial.

The NIH Pragmatic Trials Collaboratory supports pragmatic clinical trials embedded in healthcare systems to test interventions that address urgent public health problems faced by delivery systems. They involve hundreds to thousands of participants and generally include usual care as a control arm. One of the most important lessons learned through the course of these trials is that unexpected change is a given.

For more, see the section on Unanticipated Changes in the Analysis Plan chapter of the Living Textbook.

Grand Rounds August 26, 2022: The Diuretic Comparison Project: A Large Pragmatic Clinical Trial (Areef Ishani, MD, MS)

Posted on by terren.green@duke.edu

Speaker

Areef Ishani, MD MS
Director, Primary Care and Specialty Medicine Service Line
Minneapolis VA Health Care System
Professor of Medicine
University of Minnesota

 

 

Keywords

VA Point of Care Program; Diuretic Comparison Project (DCP); major adverse cardiovascular events (MACE); chlorthalidone (CTD); hydrochlorothiazide (HCTZ); Pragmatic Clinical Trial; electronic consent; comparative effectiveness studies

 

Key Points

  • The VA Point of Care Program preforms large inexpensive randomized controlled trials that are pragmatic and leverage the electronic medical record.
  • The Diuretic Comparison Project (DCP), one of the first full scale RCTs in the VA Point of Care Program, investigates if treatment with chlorthalidone (CTD) reduces major adverse cardiovascular events (MACE) compared with hydrochlorothiazide (HCTZ) in older veterans with hypertension.
  • The DCP was a multi-site pragmatic clinical trial where recruitment, consent, randomization, filling out drug orders, and assessing outcomes was done centrally by study staff, while usual care was left to the de-centralized sites without study staff present.
  • One of the biggest obstacles was a lack of a local study site investigator which made site recruitment difficult. Sites were worried about additional burden to staff. The study handled this concern by embedding the study procedures within usual care practices and streamlining workflow to keep it low intensity for the primary care provider.
  • Keys to the successful recruitment for the DCP were consent embedded in the electronic medical record, a dedicated recruitment call center outside the study team.
  • Outcomes from the DCP are being collected through a combination of manual adjudication, algorithms for primary outcome events from the Corporate data warehouse (EHR), Medicare reports, and the National Death Index.

Learn more

about the DCP study and the VA Point of Care Program.

Discussion Themes

– The DCP study will be used as a model for future comparative effectiveness studies within the VA Point of Care Program.

– The call center used in the DCP was a 5 person dedicated recruitment operation. Centralizing recruitment allows pragmatic trials to be very nimble.

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#pctGR, @Collaboratory1

Grand Rounds August 12: Equitably Including Diverse Participants in Pragmatic Clinical Trials (Consuelo H. Wilkins, MD, MSCI)

Speaker:

Consuelo H. Wilkins, MD, MSCI
Senior Vice President and Senior Associate Dean
for Health Equity and Inclusive Excellence
Professor of Medicine
Vanderbilt University Medical Center

 

Topic: Equitably Including Diverse Participants in Pragmatic Clinical Trials
Date: Friday, August 12, 2022, 1:00-2:00 p.m. ET

 

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May 16, 2022: Program Leaders Discuss Future Plans for NIH Pragmatic Trials Collaboratory

Posted on by terren.green@duke.edu

In an interview at the NIH Pragmatic Trials Collaboratory Steering Committee’s annual meeting in April, Dr. Lesley Curtis, Dr. Adrian Hernandez, and Dr. Kevin Weinfurt discussed the program’s plans for the future.

“The NIH Pragmatic Trials Collaboratory is developing the fundamental knowledge necessary to build a learning health care system,” said Hernandez. “The Collaboratory is learning how to embed clinical trials as part of healthcare delivery to accelerate evidence generation.”

Curtis, Hernandez, and Weinfurt are co-principal investigators of the NIH Pragmatic Trials Collaboratory Coordinating Center at Duke University.

In August 2022, the program plans to add 2 Core Working Groups, one focused on health equity and the second on implementation science.

“Health equity is an issue that is front-and-center for all of us,” Curtis said. “To have a group of experts in the field who can consult with new NIH Collaboratory Trials to give them guidance about best practices for addressing health equity will be fabulous.”

As the NIH Collaboratory moves forward, the program will focus its efforts on bringing in more diverse researchers and trainees into the program.

When asked about how the NIH Collaboratory has fulfilled its mission over the last 10 years, Weinfurt said, “Toward the broad goal of improving our national capacity to do embedded trials, we have improved the knowledge base that future trialists can use to develop new trials. We’ve generated tools and approaches to solve challenges that arose, trained and increased the number of researchers who are familiar with embedded pragmatic trials, and encouraged trials to develop their own networks to continue conducting these embedded trials.”

“We’ll know we’ve succeeded when all of the barriers and challenges that we’ve been working on over the last 10 years have run out,” said Curtis.

View the full interview.

See the complete materials from the 2022 Steering Committee meeting.

May 6, 2022: N-of-1 Randomized Trials: CRAVE and I-STOP-AFib as Examples (Gregory Marcus, MD, MAS)

Posted on by terren.green@duke.edu

Speaker

Gregory Marcus, MD, MAS
Professor of Medicine
University of California, San Francisco

 

 

Keywords

Eureka; AFEQT; I-STOP-AFib; CRAVE; Atrial Fibrillation; PVC; PAC; alcohol; coffee

 

Key Points

  • Atrial Fibrillation (AFib) is fairly static and chronic, but recent studies have shown a reduction in AFib with weight loss in obese patients and a reduction in AFib with a reduction in alcohol consumption.
  • In an N-of-1 study each individual participant serves as their own case control. N-of-1 studies can show how a particular individual reacts to a given condition, but not all questions can be studied with n of 1 studies.
  • The I-STOP-AFib study was a randomized completely remote N-of-1 study to assesses quality of life and test for discreet triggers of AFib. Patients chose a trigger they could readily withhold or introduce, and used a mobile app, Eureka, to determine eligibility and record their consent to participate.
  • The control group tracked their trigger. The intervention group were told to expose themselves to the trigger or avoid it and track incidence of exposure. An Alivecor ECG monitor was sent to each patient to track occurrences of AFib.
  • No difference in primary outcome was found for either group, but the intervention group had a 40% reduction in days with AFib.
  • The I-STOP-AFib study showed an increased chance of AFib immediately following consumption of alcohol, and a lower risk of AFib with consumption of caffeine.
  • The CRAVE study found no evidence that caffeine consumption increases incidence of AFib.

Discussion Themes

– Patients are very interested in N-of-1 studies and enjoy participating in a study where they can learn about themselves. Explaining how the trial works can be more difficult.

– Conducting a study involving IT, apps, and wearable technology in language other than English can take considerable planning and collaboration. Not only do study documents need to be provided in additional languages, but IT support must be available in additional languages as well.

Read more about I-STOP-AFib and CRAVE.

Tags

#pctGR, @Collaboratory1

May 5, 2022: Looking at the Landscape of National ePCT Initiatives in 2022

Posted on by terren.green@duke.edu

On April 20th and 21st, nearly 100 members of the NIH Pragmatic Trials Collaboratory met in Bethesda, Maryland, for the program’s annual Steering Committee Meeting. With 10 productive years of leading the way in embedded pragmatic clinical trials, the group had a lot to celebrate. Members led discussions on the history and evolution of pragmatic trials and shared thoughts for future priorities. In addition, leaders from five other pragmatic trial programs across the nation shared their experiences and lessons learned during a session entitled Looking at the Landscape of National ePCT Initiatives, which we recap here.

Anne Trontell, an Associate Director in the Clinical Effectiveness and Decision Science Program at the Patient-Centered Outcomes Research Institute (PCORI), spoke about PCORI’s experiences with pragmatic research initiatives. PCORI trials explore real-world decision-making about healthcare treatment options. Notable PCORI trials range in scope from asthma treatments for Black and Latinx Adults to comparative effectiveness trials of Aspirin dosing in cardiovascular disease (ADAPTABLE). Dr. Trontell stressed the value of relationships with diverse stakeholders before the start of a trial. This “prework” can help researchers better understand the issues facing research staff and participants as well as provide insight about the context, capacity, and resources available. See the slides from Dr. Trontell’s presentation for more information.

 

Robert Kerns, a Principal Investigator for the NIH-DoD-VA Pain Management Collaboratory Coordinating Center (PMC3), explained the intention of the program’s trials to inform future policy and practice regarding pain management in the VA or DOD. Dr. Kerns credits the PMC3 work groups, particularly the Biostatistics and Study Design Work Group, for the successful transition of their 11 trials to the implementation phase. PMC3 prioritized data harmonization among their trials. Use of common data collection measures and optimizing data collected from the EHR allows for easier data sharing and aggregation across projects. Building a community of trust among all stakeholders was key to the success of the projects. See slides from Dr. Kern’s presentation for more information.

 

Partha Bhattacharyya, Program Director for the National Institute on Aging and a lead developer of the National Institute on Aging IMbedded Pragmatic Alzheimer’s disease and AD-Related Dementias Clinical Trials (NIA IMPACT) Collaboratory, provided an overview of the project’s goals and accomplishments over the last 2 years. The NIA IMPACT Collaboratory supports the design and conduct of pragmatic trials for innovative dementia care. The program recognizes that understanding health system and patient experiences is essential for successful trials. Junior and senior investigators are recruited through a Faculty Scholars Program and embedded in the health systems to learn how the systems work. Stakeholders from healthcare systems and patient populations are also included in the process of developing research trials. See slides from Dr. Bhattacharyya’s presentation for more information.

 

Wendy Weber, Branch Chief for the NIH Clinical Research in Complementary and Integrative Health, introduced the NIH Helping to End Addiction Long-term (HEAL) Initiative. The program began in 2018 and provides $500 million dollars a year in funding for projects that enhance pain management or improve treatments for opioid misuse and addiction. The program has funded over 600 research projects and 26 programs including the Pragmatic and Implementation Studies for the Management of Pain to Reduce Opioid Prescribing (PRISM) program. The NIH Pragmatic Trials Collaboratory serves as the Resource Coordinating Center for PRISM. The PRISM trials focus on non-opioid interventions to manage pain and reduce reliance on opioids as well as identify effective strategies to implement evidence-based interventions. The HEAL Initiative aims to study pain and opioid use disorder as co-occurring conditions as well as promote health equity in research and treatment. See slides from Dr. Weber’s presentation for more information.

 

Gregory Simon, principal investigator of the Mental Health Research Network (MHRN), described the program’s mission to identify research questions that matter to stakeholders, find answers, and implement results for the benefit of real-world patients and providers. The MHRN began in 2010 and has now reached approximately 22 million patients in 14 health systems. Dr. Simon attributes the success of MHRN projects to longstanding, collaborative relationships with health plan and medical leaders, patient representatives, and IRBs. The project prioritizes the intersection of interests among patients, clinicians, health system leaders, and funders. See slides from Dr. Simon’s presentation for more information.

 

We will be sharing more insights form the 2022 NIH Pragmatic Trials Steering Committee Meeting over the coming weeks. All meeting materials are available online.

April 8, 2022: COVID-19 Surveillance in PCORnet: Year 2 Update (Jason Block, MD, MPH; Thomas W. Carton, PhD, MS)

Posted on by terren.green@duke.edu

Speakers

Jason Block, MD, MPH
Associate Professor
Harvard Pilgrim Health Care Institute
Harvard Medical School

Thomas W. Carton, PhD, MS
Chief Data Officer
Louisiana Public Health Institute

 

 

Keywords

PCORnet; COVID-19; Electronic health record (EHR); Surveillance data

 

Key Points

  • PCORnet is a national network of 66 million people with EHR-derived data available for research.
  • After significant database modifications to effectively include COVID-19 related data, the CDC PCORnet COVID-19 project began in April 2020 with the first query. 43 participating institutions update data monthly.
  • There have been 40 queries of the PCORnet COVID-19 data completed to date looking at descriptive trends of COVID-19 by care setting and demographics, vaccinations, chronic disease, and treatments.
  • PCORnet COVID-19 data tracks percent hospitalized and relative risk of testing positive for COVID-19 by race over time.
  • Data also shows treatment disparities with monoclonal antibodies over time by race and ethnicity. White patients or non-Hispanic patients who tested positive for COVID-19 were more likely to be treated with monoclonal antibodies than any other race or ethnicity.
  • PCORnet COVID-19 data have also been used to investigate myocarditis and pericarditis after both COVID-19 vaccination and COVID-19 infection. Males ages 12 to 29 have increased risk of cardiac complications after COVID-19 infection compared with COVID-19 vaccination.
  • PCORnet is evolving to improve the capture of information, advance analytics, and provide better collaboration between federal public health and PCORnet investigators.

Discussion Themes

    • Complete surveillance data is difficult to obtain when not all testing or vaccination is being reported.
    • State vaccination data does not always get added the EHR until the patient has another primary care encounter.
    • The ability to continue doing this kind of work relies on a national public health infrastructure.

Read more about PCORnet.

Tags

#pctGR, @Collaboratory1

January 21, 2022: Primary Palliative Care for Emergency Medicine (Corita R. Grudzen, MD, MSHS, FACEP)

Posted on by terren.green@duke.edu

Speaker

Corita R. Grudzen, MD, MSHS, FACEP
Professor, Emergency Medicine and Population Health
Associate Dean, Clinical Sciences
Deputy Director, Clinical and Translational Science Institute
Vice Chair for Research, Emergency Medicine
Ronald O. Perelman Department of Emergency Medicine
NYU Grossman School of Medicine

Keywords

Palliative Care; Stepped-Wedge study design; Emergency Department (ED); Gagne Index; PRIM-ER

 

Key Points

  • The Emergency Department is increasingly seeing older adults with serious illness rather than patients with acute trauma.
  • Primary Palliative Care for Emergency Medicine (PRIM-ER) is a stepped-wedge study partnership of 18 health systems in 33 EDs designed to change the culture and norms of emergency care to promote palliative care at home or hospice rather than admittance to the hospital.
  • The study used the Gagne Index greater than 6 to identify patients at high risk of short-term mortality. Patients with dementia did not need to meet the Gagne Index criteria to be included in the study.
  • A baseline survey, training of 2,470 emergency providers, and study intervention has been completed at all 33 sites.
  • Only .2% of ED patients in the study were admitted to hospice after their ED visit.  At 12 months post ED visit, 30% of dementia patients had died whereas 15.6% of the non-dementia chronic disease patients had died. Data analysis is ongoing.

Discussion Themes

Stepped-wedge studies present timing issues and COVID-19 increased these problems. A cluster randomized design may have been easier to implement.

 

The PRIM-ER study was considered quality improvement by the IRB, so no human subjects approval from the IRB was required.

 

The PRIM-ER next step will be developing tools for patients with dementia regarding palliative care in the ED.

 

Learn more about the PRIM-ER study.

 

Tags

#pctGR, @Collaboratory1

April 11, 2022: TSOS Implements Suicide Assessment and Monitoring Method in Pragmatic Clinical Trial

Posted on by terren.green@duke.edu

The Trauma Survivors Outcomes and Support (TSOS) trial, an NIH Pragmatic Trials Collaboratory Trial, successfully implemented a large-scale suicide assessment and monitoring method in a pragmatic clinical trial focused on collaborative mental healthcare for traumatic injury survivors. Study intervention and monitoring methods are detailed in a recent publication in Psychiatry.

TSOS researchers analyzed data collected at 25 trauma centers from 635 patients experiencing posttraumatic stress disorder (PTSD) as the result of a traumatic injury. The study used a randomized stepped-wedge design and assigned 370 patients to a control group and 265 to an intervention group.

Patients in the intervention group received proactive injury care management, psychopharmacology, and psychotherapy for PTSD and depression. All patients in both groups were evaluated at 4 timepoints: baseline and 3, 6, and 12 months after injury.

Study personnel interacting with patients participated in a 1-day training workshop to learn study methods and skills for the management of acute suicidal ideation or suicidal intent. Among other measures to assess PTSD symptoms, alcohol use, and physical function, the study team administered the Patient Health Questionnaire (PHQ-9) to screen for suicidal ideation and depression.

Source: Psychiatry. 2022; Spring. doi:10.1080/00332747.2021.1991200.

Patients from both the intervention and control groups who indicated suicidal ideation on the PHQ-9 received calls, texts, and voice messages from study personnel and referral for additional care from a clinician. Study personnel reached out to 161 control and 107 intervention group patients.

The intervention group showed a small but not significant reduction in suicidal ideation compared to the control group.

Lack of a significant treatment effect may be due to the outreach and additional care received by patients in the control group. This level of additional care could be considered a minor intervention for the control group.

Future studies may learn more about treatment differences between control and intervention groups by incorporating implementation process assessments into the design of pragmatic trials.

TSOS was supported within the NIH Collaboratory by a cooperative agreement from the National Institute of Mental Health and by the NIH Common Fund through a cooperative agreement from the Office of Strategic Coordination within the Office of the NIH Director. Learn more about the NIH Collaboratory Trials.

April 1, 2022: ICD-Pieces: Improving Care for CKD, Diabetes and Hypertension in Health Systems (Miguel A. Vazquez, MD; George (Holt) Oliver, MD, PhD)

Posted on by terren.green@duke.edu

Speaker

Miguel A. Vazquez, MD
Professor of Medicine
University of Texas Southwestern Medical Center
Dallas, TX

George (Holt) Oliver, MD, PhD
Vice President Clinical Informatics
Parkland Center for Clinical Innovation
Dallas, TX

Keywords

ICD-Pieces; Chronic kidney disease (CKD); EHR data collection; Diabetes; Hypertension

Key Points

  • ICD-Pieces focuses on the chronic conditions of Diabetes, Hypertension, and CKD. These conditions are common, under-recognized, and can have serious complications.
  • PIECES is an information technology software developed to help facilitate primary care practices provide comprehensive evidence-based care for patients with these chronic conditions.
  • Researchers enrolled 11,000 patients with CKD in the study. The interventions included controlling blood pressure with medication, avoiding hypoglycemia, use of statins, and avoidance of NSAIDs.
  • Interventions were determined to be feasible. Outcomes for study populations are to be determined with further analysis of the data.

Discussion Themes

Pragmatic trials are often practical laboratories for implementation science.

An inherent challenge of collecting data from the EHR record is delay. It may help to have part of the study team embedded in the clinical trial for the data collection aspect, or possibly to collect the data at the time of intervention rather than waiting.

 

Read more about ICD-Pieces.

 

 Tags

#pctGR, @Collaboratory1