Six NIH Collaboratory Trials—ACP PEACE, EMBED, GGC4H, HiLo, Nudge, and PRIM-ER—have recently transitioned from the planning to implementation phase of their embedded pragmatic clinical trial (ePCT). During the transition, study teams reviewed and updated their ethics and regulatory meeting minutes from discussions with the Ethics and Regulatory Core. The minutes describe ethics and regulatory issues the trials have encountered, along with approaches the trials are using for informed consent, HIPAA, and monitoring and oversight:
Ethics and regulatory issues can pose challenges to embedded pragmatic trials because of the unique nature of clinical research conducted in the setting of routine clinical care. The Ethics and Regulatory Core provides assistance to study teams as they navigate the ethics and regulatory landscape of ePCTs.
The Johns Hopkins Berman Institute of Bioethics invites applications for a Postdoctoral Fellowship in the Ethics and Regulatory Aspects of Pragmatic Clinical Trials. This position includes pursuing independent research, working alongside faculty members involved with the ethics and regulatory aspects of large-scale pragmatic clinical trials (PCTs), 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 PCTs in collaboration with Berman Institute faculty members. The Fellow will actively engage with the Ethics and Regulatory Core of the NIH Health Care Systems Research Collaboratory and the Pragmatic and Implementation Studies for the Management of Pain to Reduce Opioid Prescribing (PRISM) Resource Coordinating Center.
Qualifications: Applications are welcome from candidates who will have an MD, PhD, or JD or their equivalent by the start date of the fellowship. Applicants should not have completed their terminal degree more than 3 years before the start date of the appointment. Physicians should not have completed a formal residency training program more than 3 years by the start date of the appointment.
Start date: September 1, 2020.
Terms of Appointment: The fellowship is guaranteed for 1 year with the expectation of a second year of funding, contingent on review. Applicants may not be employed by another institution and are expected to be in residence for the duration of the appointment.
The GGC4H NIH Collaboratory Trial, now in its implementation phase, has begun enrollment of study participants. Congratulations to Drs. Kuklinski, Sterling, and Catalano and the entire GGC4H study team!
GGC4H is a cluster-randomized trial that is testing the feasibility and effectiveness of implementing Guiding Good Choices—a universal evidence-based anticipatory guidance curriculum for parents of early adolescents—in three large, integrated healthcare systems serving socioeconomically diverse families. In prior community trials, the Guiding Good Choices curriculum has been shown to prevent adolescent substance use, depressive symptoms, and delinquent behavior. This study offers an opportunity to test the intervention’s effectiveness with respect to improving adolescent behavioral health outcomes when implemented at scale in pediatric primary care within a pragmatic trial.
The NIH Health Care Systems Research Collaboratory program is excited to announce that it has received funding to serve as the Resource Coordinating Center for a new group of large-scale embedded pragmatic clinical trials (ePCTs) on pain management and reducing opioid prescribing. As part of the NIH Collaboratory, the Pragmatic and Implementation Studies for the Management of Pain to Reduce Opioid Prescribing (PRISM) Resource Coordinating Center will provide technical support and pragmatic trial expertise for the research that this program funds. PRISM trials will determine the effectiveness of multiple non-opioid interventions for treating pain and assess the impact of implementing interventions or guidelines to improve pain management and reduce reliance on opioids.
The PRISM Resource Coordinating Center funding and new research awards, described below, are part of the NIH’s Helping to End Addiction Long-term Initiative (NIH HEAL Initiative). This federal research initiative, launched in early 2018 by NIH Director Francis S. Collins, aims to apply scientific solutions to improve treatments for chronic pain, curb the rates of opioid use disorder and overdose, and achieve long-term recovery for opioid addiction.
“The NIH Collaboratory Coordinating Center is excited to be supporting these novel pragmatic trials that address an urgent health crisis. We hope the patients, clinicians, researchers, and health systems will benefit from knowledge we’ve gained supporting complex trials embedded in health care systems over the past 7 years, which will help deliver improvements in pain management to the American public faster.” – Adrian Hernandez, MD, MHS, Vice Dean for Clinical Research, Duke University School of Medicine.
The PRISM awards total approximately $35.7 million and are supported by 8 participating NIH institutes, centers, and offices. With these awards, the NIH Collaboratory will add 4 new large-scale ePCTs to its portfolio of innovative NIH Collaboratory Trials. The trials will be conducted at Boston Medical Center, Massachusetts; Kaiser Foundation Research Institute, California; Mayo Clinic, Minnesota; and University of Iowa. They include:
Non-pharmacological Options in postoperative Hospital-based And Rehabilitation pain Management (NOHARM) pragmatic clinical trial
Fibromyalgia TENS in Physical Therapy Study (TIPS): An embedded pragmatic clinical trial
Group-based mindfulness for patients with chronic low back pain in the primary care setting
Pragmatic Trial of Acupuncture for Chronic Low Back Pain in Older Adults
The NIH Collaboratory aims to improve the way clinical trials are conducted by creating a new infrastructure for collaborative research with healthcare systems. The Collaboratory has 5 Core Working Groups of experts that help research teams address challenges of conducting research embedded in clinical care, and they collect and disseminate knowledge and best practices learned throughout the process. The ultimate goal is to ensure that healthcare providers and patients can make decisions based on the best available clinical evidence.
The Coordinating Center of the National Institutes of Health (NIH) Health Care Systems Research Collaboratory is supported by the NIH Common Fund through a cooperative agreement from the Office of Strategic Coordination within the Office of the NIH Director. Read more about the NIH Collaboratory Trials and the Core Working Groups.
The NIH Collaboratory Coordinating Center launched an online survey to collect feedback from clinical investigators, healthcare system partners, and the broader research community about the Living Textbook of Pragmatic Clinical Trials. Responses to the survey will help the Coordinating Center enhance its resources for users interested in pragmatic research.
“We are eager to receive feedback on our signature resource, the Living Textbook,” said Dr. Kevin Weinfurt, co–principal investigator of the NIH Collaboratory Coordinating Center. “This feedback will help us achieve our goal of better enabling researchers to build partnerships with healthcare systems and transform how clinical research is conducted.”
The purpose of the Living Textbook, the NIH Collaboratory’s publicly available online resource at rethinkingclinicaltrials.org, is to share expert consensus regarding standard approaches, best practices, and special considerations in the design, conduct, and reporting of pragmatic clinical trials. The Living Textbook also provides information about the NIH Collaboratory program, its NIH Collaboratory Trials, and related initiatives.
The online survey will remain open until October 31, 2019.
The investigators of HiLo, an NIH Collaboratory Trial, 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 Trials 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 NIH Collaboratory Trials.
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 Trials.
The submission deadline has been extended to October 28, 2019, for a special supplement on embedded health services research in Healthcare: The Journal of Delivery Science and Innovation, the partner journal of AcademyHealth. Embedded research is a critical part of the learning health system in mining and analyzing health system data to improve patient care while also providing generalizable findings to transform the health care system at large.
This special supplement is being supported by the Department of Veterans Affairs Health Services Research & Development and will be published in March 2020. It is expected to feature 10-12 peer-reviewed articles. Ultimately, the supplement will be a resource for those aiming to improve the relevance and use of health research to improve patient care.
For details on relevant topics and how to submit your paper online, visit the journal’s special issue page.
The National Institute on Aging (NIA) Imbedded Pragmatic AD/ADRD Clinical Trials (IMPACT) Collaboratory is soliciting letters of intent for several 1-year pilot grant awards of up to $150,000. The awards will provide funds to pilot projects that aim to generate preliminary data necessary to design and conduct full-scale embedded pragmatic clinical trials of nonpharmacologic interventions in healthcare systems for persons living with Alzheimer disease and related dementias and/or their caregivers.
More than 5 million Americans are living with Alzheimer disease and related dementias. They are particularly vulnerable to receiving uncoordinated and poor-quality care, which contributes to adverse health outcomes and misuse of resources. The mission of the NIA IMPACT Collaboratory is to advance care for persons with dementia and their caregivers in real-world settings by building national capacity to conduct pragmatic clinical trials that test interventions embedded in healthcare systems.
Letters of intent to seek the pilot grant funding are due October 11, though they will be approved on a rolling basis as received. Optional informational webinars will be offered on September 26 and October 2 to provide additional information and answer questions of potential applicants. Questions can be submitted by email to impactcollaboratory@hsl.harvard.edu.
In a study using national claims data for more than 73 million pediatric visits from the NIH Collaboratory’s Distributed Research Network, researchers found uneven declines in potentially inappropriate antibiotic dispensing between 2006 and 2016. The findings suggest a need for antibiotic stewardship programs, especially interventions focusing on the use of broad-spectrum antibiotics in outpatient settings.
Although overall antibiotic prescribing among children in outpatient settings has declined since the mid-1990s, recent evidence suggests the trend may be ending. Also, it is unknown whether antibiotic stewardship efforts have influenced prescribing trends in emergency department settings.
In the new study, which included children and adolescents aged 3 months to 18 years, there was a 5% annual decrease in antibiotic prescribing in emergency departments for respiratory tract infections for which antibiotics are mostly not or never indicated. The annual decline in outpatient settings was 2%. For broad-spectrum antibiotics for respiratory tract infections for which antibiotics are mostly indicated, there were annual declines of 2% to 4% in emergency department settings, compared with an annual increase of 1% in outpatient settings. Dispensing rates were consistently higher among children younger than 12 years than among adolescents.
This work was supported by a grant from the National Center for Complementary and Integrative Health. Support was also provided within the NIH Collaboratory 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 Distributed Research Network.
At the May 2019 meeting of the NIH Collaboratory Steering Committee, we talked with Judith Carrithers, coleader of the Ethics and Regulatory Core. The task of the Core is to develop a framework for conducting embedded pragmatic clinical trials (ePCTs) in an ethical manner and in compliance with federal and state regulations. Ms. Carrithers joined the Core last year prior to the start of the yearlong planning phase for 6 new UG3 NIH Collaboratory Trials. We asked her to reflect on the Core’s progress and challenges during the past year.
Please tell us about the Core’s recent accomplishments.
The Ethics and Regulatory Core is learning how to frame ethical and regulatory issues around ePCTs while talking with each study team to learn how their trial is going to work, what informed consent considerations they may have, and, for their population, what makes the most sense within the regulatory framework. By the time I joined, the Core had already gone through the first round of UH3 NIH Collaboratory Trials, and I was able to piggyback on the learning from that experience, which informed our interviews and discussions with the new UG3 studies last summer. The regulatory framework we’re working in is a little black, a little white—and a lot of gray. For ePCTs, and clinical trials in general, within that framework there are things it’s clear you can do and cannot do, and a lot of things where you’re using your best judgment in the context of a study.
“The regulatory framework we’re working in is a little black, a little white—and a lot of gray.”
What we see with pragmatic trials across those conducted in the Collaboratory is that many are clearly minimal-risk studies, so there is the possibility of managing informed consent in a different way. A written consent form is generally required under the federal regulations for studies that present more than minimal risk to participants. But if a trial is minimal risk, we can consider a waiver of consent or alteration of the consent process if traditional written consent affects the practicability of the trial. One focus of the Core’s work has been to study when a waiver or alteration of consent is appropriate in the various types of ePCTs. In addition, we explore what other methods could be used to advise patients that they’ve been enrolled in a research study, such as broadcast notification of the research placed in prominent locations, with contact information for questions.
From the inception of the Collaboratory, both the NIH and the Office for Human Research Protections (OHRP) have been involved in helping work through how to manage these issues in a way that respects individuals enrolled in a trial while also making it possible to conduct the trial without a lengthy informed consent process when it is not required under the regulations. We will continue to look at these issues with the new NIH Collaboratory Trials to get a better feel for emerging patterns. The Core has developed several publications addressing ethics and regulatory considerations for ePCTs, and we will continue to contribute to this growing body of knowledge to share with the larger research community.
What challenges lie ahead?
A big challenge is staying aware of how the regulatory framework may change during the course of the trial, and how those changes affect the conduct of a study. For example, the revised Common Rule impacted the way IRBs review research and investigators conduct their research. It’s also important to remember what we’ve learned as a research community—for example, we’re developing better ways of giving notice to patients that they’re enrolled in a trial. And the challenge in part is that studies have used different methods of notification with varying success, and so we need a way to compile that information into an accessible format to help future study teams decide how to apply those learnings to their study.
Our challenge is to build the grammar, the framework, and the thinking process for ethics and regulatory issues in pragmatic trials. Having resources like the Living Textbook available is helpful for researchers, providing insight into how others are framing these issues and conducting their trials.
Any words of advice for new ePCT investigators?
Sort out what part of the trial is research and what part is clinical care. This is essential for study teams to define so that they know what parts of the trial are subject to the federal regulations. It’s important to segment out and treat the clinical part of the study as clinical care. Within the research part, evaluate how the regulations apply. Think carefully about your trial and work through all the pragmatic pieces, for example:
What access to the electronic health record will you need?
How will you recruit participants?
If consent is required, how will you consent participants?
One of the strengths of the Core is that we’re able to work with study teams while they’re still finalizing the design of the trial, and together build on each others’ experiences, focus on specific issues, and in some cases, change their approach in order to make the study work better in the healthcare setting or with potentially large numbers of enrollees. I think the best resource for new investigators is meeting other researchers who have done this work and hear how they addressed and overcame challenges.
The Coordinating Center of the National Institutes of Health (NIH) Health Care Systems Research Collaboratory is supported by the NIH Common Fund through a cooperative agreement from the Office of Strategic Coordination within the Office of the NIH Director. Read more about the Ethics and Regulatory Core in the Living Textbook, and learn more about the NIH Collaboratory's other Core Working Groups.
The GGC4H NIH Collaboratory Trial, now in its implementation phase, has begun enrollment of study participants. Congratulations to Drs. Kuklinski, Sterling, and Catalano and the entire GGC4H study team!
The NIH Health Care Systems Research Collaboratory program is excited to announce that it has received funding to serve as the Resource Coordinating Center for a new group of large-scale embedded pragmatic clinical trials (ePCTs) on pain management and reducing opioid prescribing. As part of the NIH Collaboratory, the 
The National Institute on Aging (NIA) Imbedded Pragmatic AD/ADRD Clinical Trials (IMPACT) Collaboratory is soliciting letters of intent for several 1-year pilot grant awards of up to $150,000. The awards will provide funds to pilot projects that aim to generate preliminary data necessary to design and conduct full-scale embedded pragmatic clinical trials of nonpharmacologic interventions in healthcare systems for persons living with Alzheimer disease and related dementias and/or their caregivers.