September 13, 2019: HiLo Awarded Continuation From Planning to Implementation Phase

The investigators of HiLo, an NIH Collaboratory Demonstration Project, 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 Demonstration Projects 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 Demonstration Projects.

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 Demonstration Projects.

September 11, 2019: Deadline Extended for Special Supplement Seeking Papers on Embedded Research

AcademyHealth

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.

September 10, 2019: NIA IMPACT Collaboratory Announces Pilot Grant Funding Opportunity

NIA IMPACT Collaboratory logoThe 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.

The request for applications is available on the NIH IMPACT Collaboratory website.

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.

August 28, 2019: Distributed Research Network Study Finds Uneven Declines in Potentially Inappropriate Pediatric Antibiotic Dispensing

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.

The study was published this week in Pharmacology Research & Perspectives.

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.

August 12, 2019: Reflections From Judith Carrithers of the NIH Collaboratory’s Ethics and Regulatory Core

Judith Carrithers, JD

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 Demonstration Projects. 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 Demonstration Projects, 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 Demonstration Projects 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.

August 8, 2019: NIH Seeks Guidance on Education Curricula Addressing Pain and Opioid Misuse and Use Disorder

The NIH released a request for information from the scientific research and medical education community and the general public regarding Centers of Excellence in Pain Education (CoEPEs), general pain education, and curricula addressing opioid misuse or use disorder.

Topics of interest include:

  • the content and delivery of institutions’ current curricula on pain, pain management, and opioid use disorder;
  • highest-priority needs for training resources and infrastructure in these areas;
  • input on the current education content of CoEPEs; and
  • comments on the importance of endorsement by accreditation bodies and professional licensure for incorporating training into institutions’ curricula.

Healthcare professionals, teaching faculty, students, professional associations, accrediting organizations, and others are invited to respond by September 1, 2019.

August 5, 2019: New Section of Living Textbook Addresses Missing Data in Intention-to-Treat Analyses

A new section of the NIH Collaboratory’s Living Textbook of Pragmatic Clinical Trials discusses challenges associated with missing data that result from noncompliance, crossover, and dropout.

Many randomized controlled trials use an intention-to-treat (ITT) analysis to measure the real-world effects of the intervention. The newly published section, Missing Data and Intention-to-Treat Analyses, considers the population-level causal effects in these trials when there is noncompliance or missing outcome data.

“One rationale for the ITT approach is that it evaluates the real-world effects of the intervention. However, a common misconception is that the ITT analysis will be unbiased regardless of crossover or missing data.”

The new section also introduces a white paper from the NIH Collaboratory’s Biostatistics and Study Design Core, “Analyses of Randomized Controlled Trials in the Presence of Noncompliance and Study Dropout.” This working document offers analysts a more detailed discussion of treatment effects in ITT analyses, including a case example and recommended strategies for estimating and reporting both ITT effects and average causal effects.

The Biostatistics and Study Design Core works with the Demonstration Project teams to create guidance and technical documents regarding study design and biostatistical issues relevant to pragmatic clinical trials.

July 26, 2019: Nudge Awarded Continuation From Planning to Implementation Phase

Dr. Michael Ho
Dr. Michael Ho
Dr. Sheana Bull
Dr. Sheana Bull

The investigators of Nudge, an NIH Collaboratory Demonstration Project, have received approval to move from the planning phase to the implementation phase of their study. Congratulations to Dr. Michael Ho, Dr. Sheana Bull, and the Nudge study team for their excellent work!

Nudge (Personalized Patient Data and Behavioral Nudges to Improve Adherence to Chronic Cardiovascular Medications) is designed to evaluate the effect of text messaging and an artificial intelligent (AI) interactive chat bot with the goal of improving medication adherence and outcomes in patients with chronic cardiovascular conditions. Up to 50% of patients do not take their cardiovascular medications as prescribed, resulting in increased morbidity, mortality, and healthcare costs.

“Ideally, if people are doing a better job of refilling their meds, they can stay more adherent to their medications, and ultimately, have better health outcomes.”
—Dr. Sheana Bull, Co-PI of Nudge

NIH Collaboratory Demonstration Projects 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 Core Working Groups and investigators from the other Demonstration Projects.

We spoke with Dr. Michael Ho, co–principal investigator of Nudge, at the NIH Collaboratory Steering Committee meeting in May about what the study team has learned during the planning phase of the trial.

What is the status of your study?

In the planning phase, we received IRB approval and developed the text message library. In the coming months, the team will continue visiting all the participating clinics and hold a stakeholder panel meeting. In the implementation phase, we will implement the trial to test the effect of nudges on medication refills as a measure of adherence.

Were there surprises during the planning phase of the study?

One of the biggest surprises was the difficulty we had getting data from pharmacies and trying to harmonize the definitions. The process was more challenging and time consuming that I expected. A pleasant surprise was the responses we got from the stakeholder and patient panels: they had great feedback on the content of the messages and were excited to interact with us.

What is an example of a challenge you were able to overcome with the help of the NIH Collaboratory Core Working Groups?

The Biostatistics and Study Design Core helped us think through our primary outcome, which is medication adherence as measured by pharmacy data. We had initially proposed including the average adherence of all medications, but we changed it to focus only on the medications for which they are non-adherent based on the advice of the Core. The Ethics and Regulatory Core also helped us, and we had several discussions about using an “opt out” approach. As a result of these discussions, we will provide all patients with an opt-out survey that the Core provided.

(Editor’s note: For more on opt-out and different approaches to informed consent, read the chapter on Consent, Disclosure, and Non-disclosure.)

What other key challenges have you faced?

Getting pharmacy data from one of our health systems has been particularly challenging because they don’t get data frequently enough; they only get data just prior to a clinic visit. We continue to have conversations about this issue.

What advice do you have for investigators conducting their first embedded pragmatic clinical trial (ePCT)?

My biggest advice to new projects in the Collaboratory is to leverage the expertise of the Cores and the other projects, particularly the ones that are further along. It’s been great to learn from the other projects, and it’s also been very helpful to hear the advice of the Cores.

Nudge is supported by the NIH Common Fund through a cooperative agreement from the Office of Strategic Coordination in the Office of the NIH Director.

July 16, 2019: ACP PEACE Trial Moves From Planning to Implementation Phase: An Interview With Dr. Angelo Volandes

Dr. Angelo Volandes
Dr. Angelo Volandes

The National Institute on Aging (NIA) recently approved the Advance Care Planning: Promoting Effective and Aligned Communication in the Elderly (ACP PEACE) trial, an NIH Collaboratory Demonstration Project, to move from the planning phase to the implementation phase. The goal of ACP PEACE is to evaluate a comprehensive advance care planning program that combines clinician communication skills training and patient video decision aids.

We spoke with Dr. Angelo Volandes, co–principal investigator of ACP PEACE with Dr. James Tulsky, at the NIH Collaboratory Steering Committee meeting in May about what the study team has learned during the planning phase of the trial.

Were there surprises during the planning phase of the study?

There were lots of surprises. The biggest surprise was that most clinicians don’t use the structured variable in the electronic health record (EHR) that we were going to use to extract our primary outcome. The workaround, which I think is actually better, is to use natural language processing (NLP) to abstract our primary outcome from the free text of the clinical note in the EHR.

The other big surprise was that oncologists really enjoyed the intervention. They have been open to the skills training and, if anything, they’ve asked for more.

What is an example of a challenge you were able to overcome with the help of the NIH Collaboratory Core Working Groups?

One challenge we encountered is related to an issue discussed in a paper by NIH Collaboratory investigators Dr. Kevin Weinfurt and Dr. Jeremy Sugarman and colleagues. It has to do with the idea of “broadcast notification.” One of our 3 participating healthcare systems asks patients if they will allow their deidentified medical record data to be used for research purposes. Every patient in that healthcare system has the option to opt out of having their deidentified data used for research purposes. Our other 2 participating healthcare systems don’t do that as a routine matter. So we needed a different approach.

Dr. James Tulsky
Dr. James Tulsky

The idea of broadcast notification—which is new and was developed in the NIH Collaboratory—is to display posters or other notices in healthcare settings that let patients know they can opt out if they have a concern about their deidentified data being shared for research purposes. Our local institutional review board (IRB) was unfamiliar with this approach. Having the Ethics and Regulatory Core help us understand the approach and educate our IRB was incredibly helpful. It was especially helpful to be able to share a published, peer-reviewed paper showing that this was an issue the NIH Collaboratory had studied.

(Editor’s note: Read the article by Weinfurt et al,  “Comparison of Approaches for Notification and Authorization in Pragmatic Clinical Research Evaluating Commonly Used Medical Practices,” in the November 2017 issue of Medical Care.)

What other key challenges have you faced?

There are always competing priorities in real-world oncology clinics. For example, there are quality improvement projects all over the place. When you’re the clinician, how do you devote the appropriate attention and time to this particular project? We feel our project is at the crux of patient-centered care, about understanding the goals, values, and beliefs of patients when it comes to serious illness care. But there are competing priorities. There can be a tension between the time you need to get the project done, for the intervention to truly reach its fruition, versus what a clinic might be willing to do.

What advice do you have for investigators conducting their first embedded pragmatic clinical trial (ePCT)?

It’s really important to get the appropriate buy-in from people in high enough positions of authority so that the project happens. It is not enough to get the chief research officer of a healthcare system to say the project is a great idea. You need the chief marketing officer, the chief executive officer, the finance people to sign off on it. When you’re in the pragmatic research world, it’s no longer just research in a controlled environment. It affects things you didn’t think about—like patient flow, revenue—and everything has to be accounted for. Make sure you get appropriate buy-in from enough stakeholders to know that you’re going to get the project done.

Also, don’t underestimate the costs of information technology (IT). For example, we need a lot more resources for our IT infrastructure now that we have switched from using a structured variable to using NLP to obtain our primary outcome. Make sure you have thought through IT needs, especially in pragmatic trials, where so much is abstracted from the EHR. Think carefully, early on, about how much time you will need from the IT group.

Anything else you want to say about ePCTs or the NIH Collaboratory?

It’s critically important to participate in the regular meetings of the Core Working Groups, to take advantage of them to help you address challenges. For example, when we encountered the problem with obtaining the primary outcome, we presented it to the EHR Core. When we had the challenge with notification and the IRB, we presented it during a meeting of the Ethics and Regulatory Core. The Core Working Groups are most useful when you openly share the challenges you are facing. That’s the way to get help from the Cores. This is my second pragmatic trial, and I’m not perfect. I put it out there because I want help from the experts.

ACP PEACE is supported within the NIH Collaboratory by a cooperative agreement from the NIA and receives logistical and technical support from the NIH Collaboratory Coordinating Center. Read more about ACP PEACE in the Living Textbook, and learn more about the NIH Collaboratory Demonstration Projects.

July 15, 2019: PRIM-ER Gains Approval to Proceed to Implementation Phase: An Interview With Dr. Corita Grudzen

Primary Palliative Care for Emergency Medicine (PRIM-ER)Dr Corita Grudzen, an NIH Collaboratory Demonstration Project, received approval this month to enter its implementation phase. PRIM-ER is a pragmatic, cluster randomized trial of a multidisciplinary primary palliative care education and decision support intervention in a diverse sample of emergency departments that differ in their specialty geriatric and palliative care capacity, geographic region, payer mix, and patient demographic characteristics.

We spoke with the principal investigator of PRIM-ER, Dr. Corita Grudzen, at the NIH Collaboratory Steering Committee meeting in May about the completion of the study’s planning phase.

What is the status of your study?

PRIM-ER is currently transitioning from a 1-year UG3 planning phase to the UH3 implementation phase, where the intervention will be tested at full scale across 33 sites in a stepped-wedge trial. Our program manager is conducting training sessions in preparation for implementing the intervention at study sites.

Were there surprises during the planning phase of the study?

There weren’t surprises so much as confirmation of what we already knew, which was that enthusiasm can go a long way. Having a detail-oriented, responsive site principal investigator is also key. When you have a well-organized team on the ground, the distance doesn’t matter as much, and all the things you think are going to get in the way don’t get in the way. Things go smoothly when you have someone who is incredibly enthusiastic, loves the content, understands the content, and is infectious about sharing the training and information with others. I think that can overcome a lot of potential barriers.

What is an example of a challenge that you were able to overcome with the help of the NIH Collaboratory Core Working Groups?

Working with the Cores was reassuring, in that they showed us we weren’t alone. We were all struggling with the same issues, and it was okay not to be perfect in the way we were attacking all the problems. We were all planning pragmatic trials, and it was okay if we showed our warts and all.

What other challenges have you faced?

Having a good team at the primary organization is really important. It’s important to have a good administrative team—a program manager, project director—who can hold down the fort, especially with pragmatic trials, when you’re traveling to a lot of sites.

What advice do you have for investigators conducting their first embedded pragmatic clinical trial?

Give yourself a break. There are a ton of imperfections in conducting embedded pragmatic trials. It’s all about the people. Pick great site principal investigators. That’s more important than anything else about the institutions. You want to have enough eligible patients that you’re going to have an impact or whatever else is involved in picking your sites. Enthusiasm and organizational savvy go a long way. Be patient and flexible and open to new iterations of what you’re doing. It feels scary at first, but I think it will serve you to be open to change.

PRIM-ER is supported within the NIH Collaboratory by cooperative agreements from NCCIH and the National Institute on Aging and receives logistical and technical support from the NIH Collaboratory Coordinating Center. Read more about PRIM-ER and the NIH Collaboratory Demonstration Projects.