A new chapter in the Living Textbook provides expert advice for investigators submitting an application for a pragmatic clinical trial to the NIH. The chapter covers finding the right Program Official and opportunity announcement, writing a strong proposal, addressing review criteria, and award status.
“First and foremost, develop and clearly define a clinical research question with a testable hypothesis and then select an experimental design best suited to answering the research question. The study question drives the research design.” —From Developing a Compelling Grant Application
Dr. Wendy Weber, the Program Officer for the NIH Collaboratory Coordinating Center, and Dr. Marcel Salive, a Program Officer from the National Institute on Aging, contributed to this chapter.
The NIH has announced two new funding opportunity announcements (FOAs) for 7 or more embedded pragmatic clinical trials that address pain management and the opioid crisis. These projects will become part of the NIH Health Care Systems Research Collaboratory as phased UG3/UH3 cooperative research.
6 – 7 large-scale embedded pragmatic trials or implementation studies designed to improve pain management and reduce unnecessary opioid prescriptions
Applications are due February 8, 2019.
The announcements are part of the NIH Heal (Helping to End Addiction Long-term) Initiative, which was created in April 2018 in an effort to speed scientific solutions for addressing the national opioid public health crisis.
Niteesh K. Choudhry, MD, PhD
Professor, Harvard Medical School
Executive Director, Center for Healthcare Delivery Sciences, Brigham and Women’s Hospital
Topic
Cluster Randomized Trials in Health Care Delivery Systems: Lessons from STIC2IT
Keywords
STIC2IT; Pragmatic clinical trial; Learning health system; Cluster randomization; Medication adherence; Telepharmacy; Electronic health record; Stakeholder engagement
Key Points
STIC2IT, a pragmatic, cluster-randomized trial, evaluated a telepharmacy intervention to improve medication adherence for people with chronic diseases.
Pragmatic aspects of STIC2IT included outcomes assessed using routinely collected data, cluster randomization by physician practice, intention-to-treat analysis, and use of the EHR to collect research data.
While medication adherence did improve in the STIC2IT intervention group, secondary clinical outcomes did not improve. Future trials within health systems should incorporate multilevel engagement across the health system, physicians and staff, and patients.
Discussion Themes
It is important to do ongoing outreach at the health system leadership level to ensure understanding and commitment to the study and keep providers aware of the trial. Study teams should be mindful of the priorities of their partner health system.
Using the EHR for research data required some upfront work building special modules and generating custom reports.
Corita R. Grudzen, MD, MSHS, FACEP
Vice Chair for Research
Associate Professor of Emergency Medicine and Population Health
Ronald O. Perelman Department of Emergency Medicine
NYU School of Medicine
Topic
Primary Palliative Care for Emergency Medicine (PRIM-ER)
Keywords
PRIM-ER; Emergency department; Palliative care; NIH Collaboratory Trial; Pragmatic trial; Stepped-wedge study design; Clinical decision support; Best practice alerts; Advance care planning
Key Point
The PRIM-ER trial is a pragmatic, cluster-randomized, stepped wedge NIH Collaboratory Trial that will implement primary palliative care in emergency medicine across a diverse group of 35 emergency departments (EDs).
PRIM-ER’s clinical decision support intervention is tailored to each ED site. The study aims to enable system, organizational, and provider change in the emergency department workflow.
The study team is identifying and preparing site champions by conducting communication skills training in serious illness for emergency physicians and staff using the EM Talk program.
Discussion Themes
It is important to consider sustainability of the intervention during the planning phase of the trial. Plan for staff turnover and how new staff will be educated and oriented to the intervention.
The volume and sophistication of best practice alerts (BPAs) received by physicians varies across U.S. emergency departments. Alert “fatigue” can be a concern.
The NIH Collaboratory recently convened a workshop to explore embedded pragmatic clinical trials comparing two or more therapeutic medical interventions. These “A vs B” trials are meant to test existing, viable treatment alternatives where there is uncertainty about which treatment is best in which populations. There are unique barriers that make these types of pragmatic trials especially challenging to implement. For the workshop, a panel of experts gathered to discuss challenges and solutions regarding partnering with healthcare systems to conduct the trials, unique legal and ethical issues, and design and operational considerations. The summary of the workshop is now available: Workshop Summary: Embedded Pragmatic Clinical Trials of Therapeutic A vs. B Interventions
Additional Resources:
Embedded pragmatic clinical trials of therapeutic A vs. B interventions workshop videocast.
Khaled El Emam, PhD
Department of Pediatrics, University of Ottawa
Children’s Hospital of Eastern Ontario Research Institute
Topic
Assessing and Reducing Risk of Re-identification When Sharing Sensitive Research Datasets
Keywords
Clinical trials; Research ethics; Data security; Data sharing; Sensitive research data; De-identified data
Key Points
The cycle of risk de-identification involves setting a risk threshold, measuring the risk, evaluating the risk, and applying transformations to reduce the risk.
The Safe Harbor method of de-identification (removal of 18 categories of data) is a legal minimum standard that does not take context into account, and may not be sufficient when sharing sensitive data publicly.
A higher standard for de-identification is the “Expert Determination” method, whereby an expert with contextual knowledge of the broader data ecosystem can determine whether the risk is “not greater than very small.”
With increasing concern about the risks of sensitive data sharing, it is important to be transparent with data participants and continue to build trust for data uses.
Discussion Themes
When is a dataset safe for sharing? What is the risk of re-identification, and how can we reduce the risk? Consider who you are releasing the data to and what other kinds of data might they have access to that could potentially lead to re-identification.
For more information on the de-identification of protected health information, visit the U.S. Department of Health and Human Services’s Guidance Regarding Methods for De-identification of Protected Health Information in Accordance with the Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule.
The Health Information Trust Alliance de-identification framework identifies 12 criteria for a successful de-identification program and methodology.
In a new video, Dr. Greg Simon explains the intraclass correlation coefficient (ICC) with an analogy to a pie eating contest. The ICC is a descriptive statistic that measures the correlations among members of a group, and it is an important tool for cluster-randomized pragmatic trials because this calculation helps determine the sample size needed to detect an effect.
“When we randomize treatments by doctors, clinics, or even whole health systems, we need to think about how things cluster, and the intraclass correlation coefficient is the measure of that clustering. When we think about sample sizes in pragmatic clinical trials, it’s important to understand what an intraclass correlation coefficient actually is.”
For most pragmatic trials, the ICC will be between 0 and 1. If the outcomes in a group are completely correlated (ICC=1), then all participants within the group are likely to have the same outcome. When ICC=1, sampling one participant from the cluster is as informative as sampling the whole cluster, and many clusters will be needed to detect an effect. If there is no correlation among members of the groups (ICC=0), then the available sample size for the study is essentially the number of participants.
In a new video, Dr. Wendy Weber, the Program Officer for the NIH Collaboratory Coordinating Center, provides some expert advice for investigators who are considering submitting an application for a pragmatic clinical trial to the NIH.
“Don’t assume that the study panel is going to understand what pragmatic means. They may have their own completely different definition than you, and it’s important that you get on the same page early on in your application.” —Wendy Weber, PhD, Acting Deputy Director, National Center for Complementary and Integrative Health (NCCIH)
The NIH Collaboratory is pleased to announce new training resources available on the Living Textbook. These resources are being shared with the research community to provide guidance about building partnerships with health systems and overcoming the challenges of conducting embedded pragmatic clinical trials (ePCTs). The materials reflect the knowledge, insight, and best practices acquired by the NIH Collaboratory program and its Demonstration Projects.
Resources include:
Materials from the inaugural ePCT Training Workshop held in February 2018 to provide training to mid- and senior-level investigators interested in conducting ePCTs
A slide presentation of the NIH Collaboratory’s goals and organizational structure along with a brief introduction to each Demonstration Project
An infographic introducing the elements of the NIH Collaboratory program and the value of engaging in pragmatic research
A slide presentation and worksheet on essential things to think about and do when designing, conducting, and disseminating ePCTs
An introductory video from NIH Collaboratory leadership on the rationale and aims for the ePCT training resources
“The workshop reinforced that there is a demand for these kinds of training opportunities across the clinical research community.” Lesley Curtis, PhD
Kidney transplantation is the preferred treatment for patients with end-stage renal disease (ESRD), but an insufficient organ supply renders dialysis the only viable treatment option for most patients. Though clinical outcomes among patients receiving dialysis have improved modestly in recent years, annual rates of hospitalization and mortality remain unacceptably high, and quality of life is poor. Poor outcomes are driven primarily by increased risk of cardiovascular disease (CVD), but interventions that improve outcomes in the general population by targeting traditional CVD risk factors have mostly failed in patients with ESRD. Current clinical practice guidelines advocate aggressive treatment of high serum phosphate to near-normal levels using dietary phosphate binders and restrictive diets. The benefits of this approach, however, are unproven, the optimal serum phosphate target remains unknown, and potential harms of aggressive treatment have not been definitively identified.
The Pragmatic Trial of Higher vs. Lower Serum Phosphate Targets in Patients Undergoing Hemodialysis (HiLo) plans to address these clinically important questions in a large, pragmatic, cluster-randomized trial that will evaluate the effects of liberalizing the serum phosphate target (“Hi”) versus maintaining aggressive phosphate control (“Lo”) for patients receiving treatment with maintenance hemodialysis.
“The question at hand is something we grapple with on a daily basis in every dialysis facility across the country. Either answer will be important new information that will help us do a better job taking care of patients and hopefully improve their quality of life.”
HiLo is led by Myles Wolf, MD, of Duke University with support from the National Institute of Diabetes and Digestive and Kidney Diseases. Read more about HiLo.
