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 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 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.

August 2, 2019: AI and the Future of Psychiatry (Murali Doraiswamy, MBBS)

Speaker

Murali Doraiswamy, MBBS
Professor of Psychiatry and Behavioral Sciences
Duke School of Medicine

Topic

AI and the Future of Psychiatry

Keywords

Artificial intelligence; Machine learning; Psychiatry; Ethical adoption of technologies; Mental health; Wearables; Mobile health

Key Points

  • There is growing evidence from randomized controlled trials of the efficacy of using digital tools in mental health diagnosis and treatment.
  • Could artificial intelligence (AI) and machine learning technologies be used to:
    • Reduce the stigma associated with mental health treatment?
    • Predict the risk for future suicide?
    • Detect Alzheimer’s years before diagnosis?
  • Categories of AI applications include low-risk apps that measure but do not diagnose, and apps used in diagnosis or treatment that must meet the same high standards of evidence as medications.
  • Clinicians still struggle with how to integrate patient data from wearable devices. AI technology might help if it could be used to synthesize the data into a risk profile for an individual.

Discussion Themes

What are the roles of stress, exercise, and sleep in mental health, and can autonomic data from wearables help explain the variance in mental health symptoms?

To develop evidence thresholds for AI, we need larger scale public-private partnerships as well as pragmatic trials addressing key clinical questions.

Read more from Dr. Doraiswamy in How to Use Technology Ethically to Increase Access to Mental Healthcare.
Tags

#AI, #pctGR, @Collaboratory1

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.

July 3, 2019: New Article Describes the Public’s Beliefs Regarding Responsibility to Participate in Research

Findings from a new article suggest that the majority of patients do not feel a personal responsibility to participate in clinical research. In the article, Kevin Weinfurt, Li Lin, and Jeremy Sugarman report the results of a national survey of nearly 3000 people regarding their attitudes towards research responsibilities as well as their trust in doctors, healthcare systems, and medical research. Ethical frameworks for learning health systems have suggested that patients have a responsibility to contribute to learning activities, including research. The findings from this survey suggest that most patients in the U.S. do not currently endorse such a responsibility.

“These data provide a useful snapshot of the public’s views toward the obligation to participate in research. It is unclear how, if at all, these views will shift with increased efforts to create mature learning health systems. And if such views do not shift, it is uncertain what that would mean for the success of learning health systems.” —Kevin Weinfurt, PhD

Read the full article: Public Views Regarding the Responsibility of Patients, Clinicians, and Institutions to Participate in Research in the U.S.

For more on alternate approaches to consent, see the Living Textbook Chapter on Consent, Disclosure, and Non-Disclosure

July 2, 2019: New Living Textbook Section on Inpatient Endpoints in Pragmatic Clinical Trials

A new section in the Living Textbook describes the considerations for using “real-world” data for inpatient-based event ascertainment. There are many sources for acquiring this information, and they have different time lags in their availability and varying degrees of error and bias. In order to use inpatient endpoints in pragmatic clinical trials, these factors must be understood during the design, conduct, and analysis phases of an embedded pragmatic clinical trial.

“The pragmatic trial community needs to collectively determine which endpoints are relevant for pragmatic trials, how they can be measured and validated, and how the accuracy of these measurement methods may impact hypothesis testing sample size estimates.” —Eisenstein et al 2019

Topics in the chapter include:

  • Pragmatic trial inpatient endpoints
  • Inpatient event data sources
  • Patient-reported data
  • Secondary data sources: EHR
  • Secondary data sources: claims
  • Case studies: ICD-Pieces, TRANSFORM-HF, ADAPTABLE, and TRANSLATE ACS
  • Data source accuracy

 

Podcast June 26, 2019: Good Clinical Practice Guidance and Pragmatic Trials: Balancing the Best of Both Worlds in the Learning Health System (Robert Mentz, MD)

June 25, 2019: GGC4H Awarded Continuation From Planning to Implementation Phase

The investigators of Guiding Good Choices for Health (GGC4H), an NIH Collaboratory Demonstration Project, have received approval to move from the planning phase to the implementation phase of their study. Congratulations to the GGC4H study team for their excellent work!

At the May 2019 NIH Collaboratory Steering Committee meeting, we talked with Drs. Stacy Sterling, Margaret Kuklinski, and Richard Catalano to hear about progress and challenges during the UG3 planning phase. The goal of GGC4H is to test the feasibility and effectiveness of implementing Guiding Good Choices—a universal evidence-based anticipatory guidance curriculum for parents of early adolescents—in 3 large, integrated healthcare systems serving socioeconomically diverse families.

“Guiding Good Choices is a tested and proven intervention in community and school-based settings. We think primary care is an ideal implementation setting because pediatricians have parents’ trust, and the AAP recommends that they offer anticipatory guidance to parents. Community and school settings do not often have the same advantages.” — Rico Catalano, Co-PI of GGC4H

In the UG3 phase, the study team partnered with 5 pediatric primary care clinics in Kaiser Permanente Northern California, Kaiser Permanente Colorado, and Henry Ford Health System, finalized the trial protocol, obtained IRB approval, and presented UG3 and pilot study findings at 2 recent national meetings: the Society for Prevention Research and the National Academy of Medicine Collaborative for Healthy Parenting in Primary Care.

Were there any surprises during the study’s planning phase?

“I’ve been pleased and surprised to see the near universal excitement for Guiding Good Choices across the 3 healthcare systems and in multiple clinics. My previous work has been with adolescents who have already started to develop problems and are clearly at risk. Often when you are engaging those teens and their parents, they are coming from a place of crisis and have a lot of anxiety and worry. With Guiding Good Choices, we’re offering it to all families of young adolescents in the pediatric clinics, and we’re heartened to see pediatricians and parents welcoming this.

“The parents and kids were so enthusiastic and excited in our pilot. It’s been extremely heartening, and I think it bodes well for the reception we’re going to get.” — Stacy Sterling, Co-PI of GGC4H

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

Our study has two core questions: Will Guiding Good Choices improve adolescent behavioral health when offered in a health care setting? Will parents in a health care setting actually enroll in Guiding Good Choices and to what degree? Our initial study design attended more to the second question, and in doing that, raised problems for the valid assessment of effectiveness. These issues could have prevented us from transitioning to the implementation phase, so we needed a good design for assessing both effectiveness and implementation. Our original plan would have included all adolescents who had well visits, but at some clinics, 25% of teens don’t have them. Our new design, developed with the IRB chair and the Biostatistics and Study Design Core, includes everyone who receives care at the pediatric clinic. Although we may enroll some people who don’t engage with the intervention, this will make the study results more generalizable and valid for both effectiveness and implementation.

What words of advice do you have for investigators conducting their first embedded PCT?

“It’s a really fasted-paced year. I think we have complementary strengths across the leaders at our sites, and that is important. Pay attention to the qualities of your team and how they can help you hit the ground running and eventually help you get across the finish line to the UH3 phase.”  — Margaret Kuklinski, Co-PI of GGC4H

GGC4H is supported within the NIH Collaboratory by a cooperative agreement from the National Center for Complementary and Integrative Health and receives logistical and technical support from the NIH Collaboratory Coordinating Center. Read more about GGC4H in the Living Textbook, and learn more about the NIH Collaboratory Demonstration Projects.