Dr. Jennifer Kawi, Dr. Jane Bolin, and Dr. Hulin Wu, principal investigators for APA-SM
A new study snapshot and updated ethics and regulatory documentation are now available for the APA-SM study. A year into the project, the research team reviewed and updated the minutes of their initial consultation with the Ethics and Regulatory Core.
APA-SM is testing a 4-week auricular point acupressure intervention for self-management of chronic pain in rural communities in South Carolina and Texas. The study will also include implementation outcomes, a cost-effectiveness analysis, and an evaluation of predictive factors for treatment response.
APA-SM is supported within the NIH Pragmatic Trials Collaboratory by the National Center for Complementary and Integrative Health, with additional oversight from the National Institute of Neurological Disorders and Stroke. Learn more about APA-SM.
Left to right: Kayla R. Mehl, Stephanie R. Morain, and Jeremy Sugarman
A new article from the NIH Pragmatic Trials Collaboratory’s Ethics and Regulatory Core offers a comprehensive scoping review of published empirical ethics research related to pragmatic clinical trials. These trials, which are designed to assess evidence-based interventions in real-world settings, present a variety of unique ethical and regulatory challenges.
The review analyzed 82 published studies of ethics issues that have been explored in the context of pragmatic clinical trials. The authors, led by Kayla Mehl at Johns Hopkins University, identified 22 distinct ethical themes, with the 5 most prevalent being consent and disclosure, risk assessment, trust and transparency, operational burdens and implementation barriers, and the role of engagement.
Consent and disclosure: Traditional written informed consent is often impractical in pragmatic trials, prompting the exploration of alternative approaches such as opt-out or general notification.
Risk assessment: Pragmatic trials present challenges in risk assessment, particularly regarding how “minimal risk” is defined and communicated, which complicates regulatory determinations and participant protections.
Trust and transparency: Trust-building practices, such as results sharing and transparent data use disclosures, are essential for fostering participant confidence.
Burdens, barriers, and costs: Institutions, investigators, and research teams face a variety of operational and logistical burdens in pragmatic trials, especially when integrating interventions into routine care and navigating ethics concerns around data governance and data sharing.
Engagement: Engagement practices in pragmatic trials have been limited and inconsistent, highlighting “a persistent gap between the ideal of inclusive, sustained collaboration and the realities of constrained resources, power dynamics, and unclear stakeholder roles.”
The authors point out that most empirical ethics research related to pragmatic trials has been concentrated in the United States and other Western countries and is heavily reliant on surveys and hypothetical scenarios. This limits the generalizability and real-world applicability of current findings. The authors advocate for future research that is geographically inclusive and that employs innovative methodologies, including nested empirical studies within ongoing pragmatic trials, to provide richer, context-sensitive insights.
Mehl completed a postdoctoral fellowship in the ethics and regulatory aspects of pragmatic clinical trials at the Berman Institute for Bioethics at Johns Hopkins University. Coauthor Stephanie Morain is a core faculty member at the Berman Institute and an associate professor of health policy and management at the Johns Hopkins Bloomberg School of Public Health. Coauthor Jeremy Sugarman is the Harvey M. Meyerhoff Professor of Bioethics and Medicine, professor of medicine, and professor of health policy and management at Johns Hopkins and the deputy director for medicine of the Berman Institute.
Denise van Hout, MD, PhD
Postdoctoral Researcher
Julius Center for Health Sciences and Primary Care
University Medical Center Utrecht, the Netherlands
Keywords
Adaptive platform trial, Regulatory efficiency, REMAP-CAP, Study design, Study startup.
Key Points
Randomised Embedded Multifactorial Adaptive Platform trial for Community-Acquired Pneumonia (REMAP-CAP) began in 2016 as a data driven analysis of ethical, administrative, and logistical and ethical (EARL) delays in clinical trials studying respiratory infections. The goal was embedded trials that are flexible, efficient, and agile to provide clinicians with high-quality evidence to make the best treatment decisions.
REMAP-CAP is a global multifactorial adaptive platform trial with a master protocol that can investigate multiple interventions in different treatment domains for a single disease.
Over 8000 patients in REMAP-CAP were randomized to 44 interventions in 16 different treatment domains between January 2019 and June 2023. Patients could be randomized to more than 1 domain resulting in 15656 randomizations. Enrollment increased during the COVID-19 pandemic.
Dr. van Hout believes that to improve clinical trials, we should treat the challenges as a scientific problem and solve them with the same rigor.
Regulatory requirements and informed consent regulations differed among sites causing confusion for the researchers about what documents should be submitted with the contract and protocol in each country. Drug labeling requirements in some countries also slowed protocol approval. EARL processes also slowed trial initiation and patient enrollment.
It was clear that overall enrollment in the UK outpaced the other 257 sites worldwide. The UK had a shorter period of time to a fully signed study contract and protocol approval compared with sites in other countries (5 days in the UK compared with 183 days in non-UK countries). This quicker time to signed contract was accomplished by either accepting the contract as-is or rejecting the contract – without negotiating small details. The UK was also 3 months faster than non-UK countries at enrolling the first patient after study approval (1 month vs 4 months, respectively) leading to more enrollment and more research questions answered.
In January of 2022 the EU centralized regulatory submission to a single portal (CTIS) to ease and speed the process of starting a new trial.
Discussion Themes
Adaptive platform trials were uncommon before the COVID-19 pandemic, but their value became clear during the pandemic. After the pandemic, REMAP-CAP focuses on different treatment domains for pneumonia. Maintaining the infrastructure for an adaptive platform trial is difficult if there is not a clear need such as there was during the COVID-19 pandemic.
Centralizing approval for trials under one government body could speed the approval process for studies. During times of high need, prioritizing one or two good trials over a lot of smaller trials can also help speed the process.
Left to right: LungSMART investigators Drs. David Wetter, Guilherme Del Fiol, and Ken Kawamoto
Ethics and regulatory onboarding documentation for 2 of the NIH Pragmatic Trials Collaboratory’s newest studies is now available. The documents include meeting minutes and supplementary materials summarizing recent discussions of ethics and regulatory issues associated with the LungSMART trial and the STEP-2 trial.
The consultations took place by video conference and included representation from the study teams, members of the NIH Collaboratory’s Ethics and Regulatory Core, NIH staff, and NIH Collaboratory Coordinating Center personnel.
LungSMART will test telehealth interventions designed to address logistical barriers and hesitancy around completing lung cancer screening among patients receiving care in community health centers in Utah.
Left to right: STEP-2 investigators Drs. Rachel Winer, Amanda Petrik, and Jasmin Tiro
The STEP-2 trial will evaluate the comparative effectiveness and cost-effectiveness of in-clinic vs mailed distribution of human papillomavirus (HPV) self-sampling kits to improve cervical cancer screening rates among patients receiving care in community health centers in Oregon and Washington.
New study snapshots and updated ethics and regulatory documentation are now available for the AIM-CP, ARBOR-Telehealth, and RAMP trials. The 3 NIH Collaboratory Trials, all supported through the NIH HEAL Initiative℠, or Helping to End Addiction Long-Term Initiative℠, reflect a special emphasis on developing strategies for the management of chronic pain in rural and remote populations. The trials have transitioned from the UG3 planning phase to the UH3 implementation phase.
“There are many known disparities between urban and rural populations,” said Karen Kehl, a program director at the National Institute of Nursing Research (NINR), in an interview at the NIH Pragmatic Trials Collaboratory’s 2024 Annual Steering Committee Meeting. “And when we talk about chronic pain, we know that there’s a higher incidence and a higher severity of pain in rural populations, and yet they don’t have access to many of the effective solutions that we have,” Kehl added.
AIM-CP
AIM-CP is testing the implementation of a care management program to address disparate access to nonpharmacological treatments for chronic pain in rural populations. The principal investigators are Sebastian Tong and Kushang Patel of the University of Washington. The study is supported by NINR.
ARBOR-Telehealth is evaluating the use of a telehealth physical therapy strategy for patients who present to primary care clinics with low back pain in rural communities. The principal investigators are Richard Skolasky and Kevin McLaughlin of Johns Hopkins University. The study is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases.
RAMP is evaluating the use of a 12-week mind-body skills training program for rural veterans with pain within the VA’s Whole Health initiative, including a one-on-one session with a Whole Health coach followed by 11 weekly group sessions to include prerecorded expert-led education videos, mind-body skills training and practice, and group discussions. The principal investigators are Diana Burgess and Roni Evans of the University of Minnesota and Katherine Hadlandsmyth of the University of Iowa. The study is supported by NINR.
Ethics and regulatory onboarding documentation for one of the NIH Pragmatic Trials Collaboratory’s newest trials is now available. The documents include meeting minutes and supplementary materials summarizing recent discussions of ethics and regulatory issues associated with the APA-SM trial.
The consultations took place by video conference and included representation from the study team, members of the NIH Collaboratory’s Ethics and Regulatory Core, NIH staff, and NIH Collaboratory Coordinating Center personnel.
APA-SM will test a 4-week auricular point acupressure intervention for self-management of chronic pain in rural communities in South Carolina and Texas. The study will also include implementation outcomes, a cost-effectiveness analysis, and an evaluation of predictive factors for treatment response.
APA-SM is supported through the NIH HEAL Initiative with administrative oversight by the National Center for Complementary and Integrative Health and the National Institute of Neurological Disorders and Stroke.
Ethics and regulatory documentation for all of the NIH Collaboratory Trials is available on our Data and Resource Sharing page.
Updated study snapshots and ethics and regulatory documentation are now available for the BEST-ICU and Chat 4 Heart Health trials. Both of these NIH Collaboratory Trials are supported by awards from the National Heart, Lung, and Blood Institute.
BEST-ICU transitioned from the planning phase to the implementation phase during the summer. As part of the transition, the study team reviewed and updated the minutes of their initial consultation with the Ethics and Regulatory Core. BEST-ICU is evaluating 2 strategies grounded in behavioral economics theory and implementation science to increase ABCDEF bundle adoption in the intensive care unit and improve care for critically ill adults across a variety of healthcare systems, particularly those serving populations with known health disparities. The ABCDEF bundle is a multicomponent, evidence-based intervention to improve team-based care.
Chat 4 Heart Health also transitioned from planning to implementation this summer. The trial is testing the comparative effectiveness of 3 text messaging delivery strategies that have been shown to improve individuals’ self-management health behaviors, including physical activity and medication adherence. The study will provide evidence regarding the best population-based strategy for universal delivery to engage patients in self-management to improve the American Heart Association’s “Life’s Essential 8” measures for improving and maintaining cardiovascular health.
The Johns Hopkins Berman Institute of Bioethics invites applications for a Postdoctoral Fellowship in Clinical Research Ethics and Regulation. This position includes pursuing independent research, working alongside faculty members involved with the ethics and regulatory aspects of large-scale pragmatic clinical trials and participating in the Hecht-Levi Postdoctoral Fellowship in Bioethics.
The postdoctoral fellow is expected to pursue one or more projects addressing the ethics and regulatory aspects of pragmatic clinical trials in collaboration with Berman Institute faculty members. The Fellow will actively engage with the Ethics and Regulatory Core of the NIH Pragmatic Trials Collaboratory.
Hecht‐Levi Postdoctoral Fellows participate in a wide range of activities at Johns Hopkins, and have access to various benefits including:
Weekly seminars, presentations and discussions with leading academic and policy makers;
Individualized research program;
Bioethics coursework through the Berman Institute’s Master in Bioethics program;
Postdoctoral mentoring in bioethics;
Teaching (serve as course director, co-director, or TA depending on experience and background);
Professional development training; and
Berman Institute’s outreach efforts via social media.
In an invited commentary published this month in Circulation: Cardiovascular Quality and Outcomes, authors from the NIH Pragmatic Trials Collaboratory’s Ethics and Regulatory Core describe the recurring and emerging ethical issues in pragmatic clinical trials.
Coauthors Caleigh Propes, Stephanie Morain, and Pearl O’Rourke discuss 3 key challenges facing pragmatic trials researchers:
waivers and alterations of informed consent and their implications for transparency
managing and responding to “collateral findings” in pragmatic trials
representativeness of study populations, and the risk of reinforcing existing inequalities in healthcare delivery systems
Each of the 3 challenges has taken on increasing importance for the NIH Collaboratory’s Ethics and Regulatory Core. For example, the group completed a 2-year multimethod investigation of collateral findings in pragmatic trials, identifying the core themes and proposing directions for future research.
Propes is a doctoral student in bioethics and health policy, and Morain is an associate professor of health policy and management and a core faculty member of the Berman Institute of Bioethics—both at Johns Hopkins University. O’Rourke is a retired bioethicist who served as the director of human research affairs at Partners HealthCare Systems in Boston and as an associate professor of pediatrics at Harvard Medical School.
The Grand Rounds session will be held on Friday, April 26, 2024, at 1:00 pm eastern.
Milner is a regulatory policy adviser in the FDA's Office of Clinical Policy. Casey is an assistant professor of medicine and the director of the coordinating center for the Pragmatic Critical Care Research Group at Vanderbilt University Medical Center. Semler is an associate professor of medicine and codirector of the Vanderbilt Center for Learning Healthcare at Vanderbilt University Medical Center.
Ethics and regulatory onboarding documentation for one of the NIH Pragmatic Trials Collaboratory’s newest trials is now available. The documents include meeting minutes and supplementary materials summarizing recent discussions of ethics and regulatory issues associated with the APA-SM trial.
The Johns Hopkins Berman Institute of Bioethics is accepting applications for its 
In an invited commentary 