On April 22 and 23, 2020, more than 90 participants joined the online Steering Committee meeting to hear about the evolution of the embedded PCT (ePCT) ecosystem, discuss how to strengthen partnerships across the ecosystem, and identify approaches and lessons that will help inform and broaden the ecosystem. All presentations are available for downloading.
study design
April 24, 2020: The RECOVERY Trial: A UK National Platform Trial of Potential Treatments for Patients Hospitalised with COVID-19 (Martin Landray, PhD, FRCP)
Speaker
Martin Landray, PhD, FRCP
Professor of Medicine & Epidemiology
Nuffield Department of Population Health
University of Oxford, UK
Topic
The RECOVERY Trial: A UK National Platform Trial of Potential Treatments for Patients Hospitalised with COVID-19
Keywords
Coronavirus; Virus pandemic; COVID-19; SARS-CoV-2; RECOVERY Trial; Randomized trial; Epidemiology
Key Points
- Between March 10 and April 3, 2020, the RECOVERY team developed the protocol, obtained regulatory and ethics approval, and enrolled 1,000 patients.
- COVID-19 presents an unprecedented clinical challenge to the health system, staff, and patients. Even moderate effects from this study will be worthwhile in the generation of robust evidence.
- RECOVERY follow up will involve linkage to national data sources for vital status and death certificates; coded hospital episode statistics (diagnoses, procedures); intensive care audit data and SARS-CoV-2 PCR laboratory results; and primary care and national outpatient prescribing data.
Discussion Themes
Informed consent for participants in the RECOVERY trial consists of a 2-page information sheet and single form written in plain language.
The urgency of this pandemic requires everyone to focus on what matters and leave orthodoxy, habits, and traditional practices behind. Our mindset has been altered by the COVID-19 disruptions and this public health crisis of extraordinary proportion.
For more information, visit the RECOVERY Trial website.
Tags
#pctGR, #COVID19, @Collaboratory1
April 23, 2020: New Workshop Summary on the Design and Analysis of Pragmatic Clinical Trials
In 2019, NIH Health Care Systems Research Collaboratory held a comprehensive workshop to explore and discuss statistical issues encountered with embedded pragmatic clinical trials (ePCTs). The new Workshop Summary describes panel discussions with the principal investigators and statisticians of NIH Collaboratory Trials and the challenges and solutions encountered during the design and analysis of their trials.
The 4 panel discussions covered the following topics:
- Measurement and Data: Outcomes, Exposures, and Subgroups Based on EHR Data
- To Cluster or Not to Cluster?
- Choosing a Parallel Group or Stepped-Wedge Design
- Unique Complications
This Workshop Summary also provides lessons learned and recommends tools to help others design and analyze future ePCTs. For more on the design and analysis of pragmatic clinical trials, see the tools provided by the Biostatistics and Study Design Core and Living Textbook chapters on Experimental Designs and Randomization Schemes and Analysis Plans.
April 22, 2020: New Article Details the Design of ADAPTABLE, PCORnet’s First Pragmatic Trial
A new article in JAMA Cardiology discusses the design of ADAPTABLE, a pragmatic clinical trial (PCT) which strives to answer a three-decade-old question with great potential significance for public health. ADAPTABLE is the first PCT to use many of the data-driven and patient-centric capabilities of the National Patient-Centered Clinical Research Network (PCORnet).
Researchers in ADAPTABLE pursued the unanswered question of whether a low dose or high dose of aspirin is optimal for secondary prevention of atherosclerotic cardiovascular disease. Complexities of running a randomized clinical trial and the expenses associated with it have previously prevented researchers from answering this question.
The capabilities of PCORnet have aided in this research. Though not all randomized clinical trials can be designed as PCTs, ADAPTABLE demonstrates the possibility of incorporating pragmatic elements into future studies with the goal of producing real-world evidence.
A key objective of involving PCORnet in ADAPTABLE was the ability for large-scale recruitment (15,000 participants) using electronic health records and electronic informed consent. The PCORnet component permitted complete electronic participation, from randomization to data collection. Patients reported their own data during scheduled electronic follow-ups, which replaced conventional follow-up visits.
NIH Collaboratory Coordinating Center co–principal investigator Dr. Adrian Hernandez also serves as co–principal investigator of ADAPTABLE and contributed to the article.
See the accompanying editorial describing lessons learned from the design features of ADAPTABLE.
April 17, 2020: The HERO Program: PCORnet® at Work to Create a Healthcare Worker Community for Rapid Cycle Evidence (Nakela Cook, MD, MPH; Josie Briggs, MD; Susanna Naggie, MD; Emily O’Brien, PhD; Russell Rothman, MD; Chris Forrest, MD, PhD)
Speakers
Nakela Cook, MD, MPH
Executive Director
PCORI
Josie Briggs, MD
Acting Chief Science Director
PCORI
Susanna Naggie, MD
Principal Investigator, HERO-HCQ Clinical Trial
Duke University
Emily O’Brien, PhD
Principal Investigator, HERO-Registry
Duke University
Russell Rothman, MD, MPP
Chair, HERO Steering Committee
Vanderbilt University
Chris Forrest, MD, PhD
Chair, HERO Registry
Children’s Hospital of Pennsylvania
Topic
The HERO Program: PCORnet® at Work to Create a Healthcare Worker Community for Rapid Cycle Evidence
Keywords
Coronavirus; Virus pandemic; COVID-19; PCORI; Patient-Centered Outcomes Research Institute; Frontline health workers; Hydroxychloroquine; Healthcare systems; HERO-HCQ
Key Points
- With the onset of the coronavirus pandemic, the U.S. healthcare system faces an unprecedented stress test to adapt to meet new demands.
- Those on the frontline of caring for patients—healthcare workers—are at risk of developing or transmitting COVID-19. Evidence is urgently needed to keep healthcare workers and their families safe and healthy, which ultimately will help protect us all.
- The HERO (Healthcare Worker Exposure Response & Outcomes) Program has three broad focus areas to develop rapid evidence around healthcare workers’ outcomes related to COVID-19:
- Emphasis on the adaptations in how healthcare is delivered
- Emphasis on vulnerable populations
- Emphasis on the well-being of the healthcare worker
- HERO will consist of a registry study of healthcare workers and a randomized controlled trial called HERO-HCQ that will evaluate the safety and efficacy of hydroxychloroquine to prevent COVID-19 clinical infections in healthcare workers.
Discussion Themes
The goal of the HERO registry is to understand all aspects of healthcare workers’ lives—those with direct impact and those with indirect impact.
What mechanisms are you envisioning for new study proposals that would be conducted via the HERO platform?
Serologic testing will have a significant role in understanding prior infection and potential immunity.
The HERO Registry is open to any healthcare worker to join at https://heroesresearch.org/. Enrollment takes only a few minutes; participation is free and voluntary. It is not restricted by profession. All data are kept confidential.
Tags
#HeroRegistry, #pctGR, @Collaboratory1, @PCORI, @PCORnetwork, @HeroesResearch
April 16, 2020: Why Randomized A vs B Comparisons Remain Uncommon in Clinical Trials
In an article published today in the New England Journal of Medicine, NIH Collaboratory investigators Drs. Greg Simon, Rich Platt, and Adrian Hernandez describe why it has been so challenging to meet the National Academy of Medicine’s 2020 goal for the development of a learning health system. If the goal had been met, 90% of clinical decisions would be based on accurate evidence gathered from health systems that continually learn from data collected as part of routine care.
Absent such evidence, the type of care provided is determined by the haphazard influences of financial incentives, clinicians’ anecdotal experiences, and patients’ or clinicians’ exposure to marketing messages. — Simon et al, New England Journal of Medicine, April 16, 2020
Most pragmatic trials, including the NIH Collaboratory Demonstration Projects and clinical trials conducted through the National Patient-Centered Clinical Research Network (PCORnet), have compared standard care with proposed improvements to standard care, or “A vs A-plus trials.” Trials that compare 2 alternative treatments that are in current use, or “A vs B trials,” are rarely done.
The authors describe both the barriers and the potential solutions for the development of more A vs B pragmatic clinical trials in pursuit of a learning health system.
“Achievement of the NAM’s goal of basing 90% of clinical decisions on accurate evidence remains distant, and meaningful progress will involve engagement by many parties,” write Simon and colleagues. “It will require health system leaders to consider rigorous evidence generation a core function of ordinary health care, research funders to prioritize practical questions relevant to population health and to support infrastructure for embedded research, research regulators to align consent procedures with incremental risks of research, and researchers to ask real-world questions that patients, caregivers, and clinicians want answered. But the first step is for everyone involved to honestly acknowledge the lack of evidence supporting the majority of common medical decisions and the urgent need for more relevant and efficient clinical research,” the authors continue.
The impetus for the article was an NIH Collaboratory workshop, Embedded Pragmatic Clinical Trials of Therapeutic A vs B Interventions. The workshop explored challenges and strategies for planning and implementing embedded pragmatic clinical trials that compare 2 or more therapeutic medical regimens.
The authors of the article are Adrian F. Hernandez, MD, MHS, professor of medicine and vice dean for clinical Research in the Duke University School of Medicine; Gregory E. Simon, MD, MPH, of the Kaiser Permanente Washington Health Research Institute; and Richard Platt, MD, MSc, of the Harvard Pilgrim Health Care Institute. All 3 institutions are part of the NIH Collaboratory Coordinating Center.
April 10, 2020: Hydroxychloroquine for the Early Treatment of COVID-19 in Hospitalized Adults: A Multicenter Randomized Clinical Trial (Sean Collins, MD, MSc)
Speaker
Sean Collins, MD, MSc
Professor and Executive Vice Chair
Department of Emergency Medicine
Director, Center for Emergency Care Research and Innovation
Vanderbilt University Medical Center
Topic
Hydroxychloroquine for the Early Treatment of COVID-19 in Hospitalized Adults: A Multicenter Randomized Clinical Trial
Keywords
Coronavirus; Virus pandemic; COVID-19; Randomized controlled trial; Acute respiratory distress syndrome (ARDS); Hydroxychloroquine; FDA; Emergency Use Authorization; ORCHID study
Key Points
- Hydroxychloroquine is a biologically plausible agent for early treatment of acute respiratory distress syndrome in patients with COVID-19, but its effects remain to be evaluated in a high-quality, multicenter, blinded, placebo-controlled trial.
- In an Emergency Use Authorization, the FDA has encouraged the conduct and participation in randomized controlled clinical trials that may produce evidence concerning the effectiveness of hydroxychloroquine in treating patients with COVID-19.
- Trial results of the effects of this agent will be informative, whether showing benefit or harm.
Discussion Themes
The study team for this trial determined that one-to-one randomization would yield the best data quickly.
Efficacy and safety of hydroxychloroquine must be closely monitored in a health setting.
This is not the only study of chloroquine going on around the world; is there any collaboration with other studies?
Because of the urgency of the pandemic, people are collaborating on a level never seen before. We have a common goal and must maintain momentum through accelerating clinical trials with large teams of parallel studies.
Read more about this COVID-19 study at NCT04332991.
Tags
#pctGR, @Collaboratory1
April 6, 2020: Convening Pain Management Expertise in the Patient-Centered Outcomes Core: An Interview With Dr. Kevin Weinfurt
The Collaboratory recently interviewed Kevin Weinfurt, PhD, co-chair of the Patient-Centered Outcomes Core working group, to hear about the Core’s plans for supporting the PRISM Demonstration Projects. In this video, Dr. Weinfurt says one challenge for embedded trials of pain is in obtaining high-quality, complete patient-reported outcome data on pain intensity and functioning. Along with other national initiatives focused on pain research, such as the NIH-DoD-VA Pain Management Collaboratory, a chief task of the Core will be to look at efforts to harmonize pain outcomes across studies.
“The Core serves as a convener of expertise in pain management within the Collaboratory. We keep an eye on issues across the Demonstration Projects that might also be of interest to the broader pragmatic trial community.”
Read more about the work of the Patient-Centered Outcomes Core, and view other interviews about the HEAL Initiative and PRISM Demonstration Projects.
March 27, 2020: Living Textbook Grand Rounds Series: Part 3-Tips for Putting Together a Successful PCT Grant Application (Wendy Weber, ND, PhD, MPH)
Speaker
Wendy Weber, ND, PhD, MPH
Branch Chief, Clinical Research Branch
Division of Extramural Research
National Center for Complementary and Integrative Health (NCCIH)
Topic
Tips for Putting Together a Successful PCT Grant Application
Keywords
Pragmatic clinical trials; Embedded PCTs; Healthcare systems; NIH; Scientific officers; Funding opportunity announcement; Request for application
Key Points
- Investigators interested in developing a compelling grant application for a pragmatic clinical trial (PCT) should consider these tips:
- First, confirm that a PCT is the best study design to answer your research question.
- From the NIH’s 27 Institutes and Centers, find the one that matches your disease area, organ system, or stage of life—and talk with the program official.
- Also find the right funding opportunity announcement (FOA) and tailor your application to address all the FOA-specific instructions and review criteria.
- Do not assume that the study panel is going to understand what pragmatic means; they may have a completely different definition. It is important that you get on the same page early in the application.
- In your application, make sure you justify the research, include pilot data, address potential overlaps, reduce complexity, ensure the aims will advance the field, choose expert personnel for a multidisciplinary team, link data collection and analysis to aims, and justify the use of multiple sites and sample size.
Discussion Themes
For some urgent clinical problems, a PCT may be the only study design that can answer the research question.
Phased awards can be helpful. Determine the key elements of your trial to test in the planning phase. It’s important to “fail quickly”—not in the implementation phase. Applicants should identify milestones in the planning phase that will help convince reviewers their study will be feasible.
Because PCTs take place in changing conditions and real-world healthcare settings, they are not necessarily easier to implement than a traditional efficacy trial.
For more information, visit the Living Textbook’s Developing a Compelling Grant Application.
Tags
#pctGR, @Collaboratory1
March 31, 2020: Engagement in PCTs: Considerations from the Collaboratory’s Ethics and Regulatory Core
A new document from the Ethics and Regulatory Core is available that provides considerations around determining which individuals or groups are engaged in research in pragmatic clinical trials (PCTs). Developed for investigators designing and conducting PCTs as well as institutional review boards overseeing them, the document introduces these questions in relation to research subjects, study team members, and service providers:
- Which individuals/groups are included in the research?
- Are these individuals/groups research subjects, study team members, or service providers?
- Why does it matter how the individuals/groups are categorized for the research?
Download Engagement in Research for Pragmatic Clinical Trials.