AcademyHealth is accepting abstracts for the 14th Annual Conference on the Science of Dissemination and Implementation in Health until July 27, 2021. This year’s meeting will be held virtually from December 14 to 16.
Read the complete call for abstracts.
The theme of this year’s virtual online meeting is “Broadening Horizons for Impact: Incorporating Multisectoral Approaches into D&I Science.” The annual conference is cohosted by the NIH and AcademyHealth with the goal of realizing “the full potential of evidence to optimize health and health care by bridging the gap between research, practice, and policy.”
In a new article in Healthcare’s special issue on embedded research, Leah Tuzzio and colleagues use experiences from the NIH Collaboratory to describe how quality improvement activities may pose challenges for embedded pragmatic clinical trials (ePCTs), especially if there are overlapping goals and timelines.
For ePCTs to be rigorous, study teams must monitor, adapt, and respond to QI during the design and the trial implementation. Both ePCTs and QI happen within the same context and aim to improve patient care, and they are inherently interconnected. — Tuzzio et al, Healthcare, 2021
ePCTs tend to be larger and more broadly generalizable than quality improvement initiatives and may generate high-quality evidence for care and clinical practice guidelines. Quality improvement initiatives may address the same high-impact health questions, but if they co-occur with ePCTs, they may dilute or confound the ability to detect change. As a result, study teams may need to monitor, adapt, and respond to quality improvement initiatives during the design and conduct of the trial. The authors suggest that routine collaboration with healthcare system stakeholders can help align research and quality improvement to support high-quality, patient-centered care.
Publication of the special issue was supported by AcademyHealth.
Adaptive platform trials focus on a specific disease, asking: What is the best treatment for a unique patient with this disease? Such trials involve making adaptations to accruing data and conducting frequent interim analyses. Multiple interventions can be evaluated at the same time, and study arms can be staggered.
An adaptive platform is well suited to studying COVID-19 interventions. The PRINCIPLE trial aims to evaluate whether repurposed drugs can make a difference with early intervention for patients with COVID-19 symptoms. It is a nationwide (UK) clinical study from the University of Oxford to find treatments for recovery at home.
Adaptive platform trials have the potential to evaluate treatments quickly (to determine early superiority or futility) and the flexibility to add or remove treatments during the ongoing study. The use of “response adaptive randomization” allocates more patients to interventions having better outcomes.
Because most people with COVID-19 are managed in the community, community treatments may have the widest reach and impact. PRINCIPLE takes “research to the patient,” with online consent, study materials that are sent directly to patients, and patient self-sampling. Participation in the trial is not limited to where people receive healthcare.
Discussion Themes
The “inverse research participation law” (proposed by Julian Tudor Hart) posits that access to research is often inversely proportional to a participant’s potential contribution and to where the research findings should be most applicable.
A pragmatic trial should ensure that the comparator group is as close to usual care as possible. So while the trial design does not allow an understanding of the mechanisms behind any observed effect, it is the best design to find out what would happen if the treatment were used in the real world.
The PRINCIPLE study team was able to do intensive remote monitoring of patients online, by telephone, trial partner, or using routinely collected data.
Read more about PRINCIPLE and adaptive platform trials.
Clyde W. Yancy, MD, MSc Vice Dean, Diversity and Inclusion Professor of Medicine Chief, Cardiology Feinberg School of Medicine Northwestern University
Guest Moderator: Kanecia Zimmerman, MD Associate Professor of Pediatrics Duke University School of Medicine
Topic
Diverse Representation Among Clinical Trial Participants: Why It Is Important and How Can We Improve
Keywords
Clinical trials; Health outcomes; Racial disparities; Diverse participant recruitment; Disease burden; Cardiovascular disease
Key Points
The reason we do clinical research is to improve the health of the community. But trials do not represent the full spectrum of the community with respect to elderly patients, minorities, and women. In excluding overlooked populations, trials do not explore—or generate appropriate evidence about—the totality of a health intervention’s benefit.
It is urgent that we advance the overall “research IQ” of the populace, thus overcoming a legacy of mistrust of the research enterprise and reducing barriers to participation in clinical trials.
Among the steps to advance diversity in clinical trials:
Consider economic incentives or penalties by FDA or payers
Revisit the design of trials, selection of investigators and sites, and geographic balance
Recruit and train more diverse coordinator and investigator research teams
Engage with peer investigators outside the U.S. to target more race/ethnicity diversity and gender balance in clinical trial recruitment
Incorporate novel digital health technologies to expand the pool of potential research participants
Discussion Themes
In cardiovascular health, having diverse representation in clinical trials is clinically necessary to address ongoing disparities. It’s essential that trialists study the condition in populations that have borne an outsized burden of disease.
To diversify and expand the populations we study, we must think differently and be intentional from the outset. When we start to get truly diverse representation in clinical trials—when we actually study the person who has the condition—there will be robust enthusiasm and a greater sense of purpose throughout the clinical trial ecosystem.
Adaptive trial designs could be used to see if recruitment is on target and then make real-time adjustments to catch missing populations.
In thinking about accountability, what is the role of journals and ClinicalTrials.gov on reporting of race/ethnicity of both participants and investigators?
Read more about how to enhance diversity in clinical trials in recent FDA guidance and in cardiovascular trials in particular in Ortega et al., Circulation, 2019.
Derek C. Angus, MD, MPH Chief Healthcare Innovation Officer, University of Pittsburgh Medical Center Associate Vice Chancellor for Healthcare Innovation, University of Pittsburgh Schools of the Health Sciences Distinguished Professor and Mitchell P. Fink Endowed Chair Department of Critical Care Medicine University of Pittsburgh and UPMC
Topic
Lessons from COVID-19: The First Year of the REMAP-CAP Global Adaptive Platform Trial
Keywords
COVID-19; REMAP-CAP; Adaptive platform trial; Learning health system; Response-adaptive randomization
Key Points
REMAP-CAP (Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia) uses a novel adaptive trial design to evaluate a number of treatment options simultaneously and efficiently. This design is able to adapt in the event of pandemics, and increases the likelihood that patients will receive the treatment that is most likely to be effective for them.
REMAP-CAP is an international trial with multiple coordinating centers and 300 sites in 19 countries.
The REMAP-CAP trial was initially drafted with a prespecified Pandemic Appendix to be activated in the event of an emergent pandemic. In 2020, this mode was activated as REMAP-COVID, which expanded enrollment to include all hospitalized patients with clinically diagnosed or microbiologically confirmed COVID-19.
While adaptive platform trials are likely here to stay, there is a need to build comfort with the modeling, inference, and interpretation; build appropriate infrastructure to keep up with the power of the engine; and invest in common data models.
Discussion Themes
It is possible to design adaptive platform trials with a smaller sample size, depending on the research question.
How did you convince study teams to join your effort rather than start their own?
In the future, small trials could be hosted within the REMAP-CAP adaptive platform.
Given the massive inertia in investment to develop adaptive infrastructures, what are your thoughts for funders across institutions and nations?
Read more about REMAP-CAP and how the REMAP-CAP platform was modified to respond to the COVID-19 pandemic.
Susan S. Ellenberg, PhD Professor of Biostatistics, Medical Ethics, and Health Policy Perelman School of Medicine University of Pennsylvania
Topic
Data and Safety Monitoring Boards for Trials of COVID-19 Vaccines: The Challenges
Keywords
COVID-19; Data Monitoring Committee (DMC); Data and Safety Monitoring Board (DSMB); Pandemic; Vaccine trials; Monitoring boundaries; Safety and efficacy; NIH
Key Points
With COVID-19, everyone, globally, is an “affected community.” This brings a strong sense of urgency for DSMBs.
Several COVID-19 vaccine candidates are studied under the NIH umbrella. A single DSMB, constituted in mid-2020, oversees all these COVID-19 trials and reports to that trial’s Oversight Group.
Subgroup issues have been important in COVID-19 vaccine trials. The DSMB monitors carefully for representation of subgroups of interest in trial participants, including those over age 65, Black, Hispanic, and participants with comorbidities that may predispose them to more serious disease.
Discussion Themes
Has there been pressure to prematurely discontinue any of the COVID-19 vaccine trials?
How accurate is the post-vaccine data being collected—especially since these vaccines have only emergency use authorization?
What are your thoughts on future trial design if we have another pandemic?
See more COVID-19 resources for researchers and access other webinars in the COVID-19 Grand Rounds series on the Collaboratory’s COVID-19 resource page. Read more about data and safety monitoring in the Living Textbook.
Sebastian Schneeweiss, MD, ScD Chief, Division of Pharmacoepidemiology and Pharmacoeconomics Department of Medicine, Brigham and Women’s Hospital Professor of Medicine, Harvard Medical School Professor in Epidemiology, Harvard T.H. Chan School of Public Health
Topic
Calibrating Real-World Evidence Against RCT Evidence: Early Learnings from RCT-DUPLICATE
While RCTs are an accepted research study design to establish the efficacy of medical products, RWE studies can complement the evidence generated by RCTs, as well as expand the line of inquiry around population, endpoints, treatment patterns, and comparators.
The RCT-DUPLICATE study aimed to understand and improve the validity of RWE studies for regulatory decision making. One objective was to identify factors that predictably increase the validity of such studies.
In RCT-DUPLICATE, RWE studies were designed to emulate 20 target RCTs. The regulatory-standard RCTs for replication underwent feasibility checks and quality assessments.
With data that are fit-for-purpose and proper design and analysis, nonrandomized RWE studies usually come to the same conclusion as the RCT about a drug’s treatment effect.
In any emulation, despite best efforts, there will remain differences in population, measurement, and drug use. Data fit-for-purpose and study design choices are the most important considerations for emulation success.
Discussion Themes
Initial findings of RCT-DUPLICATE identify circumstances when RWE may offer causal insights in situations where RCT data are either not available or cannot be quickly or feasibly generated.
Can this approach be used to predict results for a new entity?
It will be useful to establish a repository of case studies to increase the predictability of future RWE studies; increase the use of common methodological approaches to emulate target trials; and point out areas that are currently difficult to address with RWE.
Lesley Curtis, PhD Professor in Population Health Sciences Department of Population Health Sciences Duke University School of Medicine
Bradley Hammill, DrPH Associate Professor in Population Health Sciences Department of Population Health Sciences Duke University School of Medicine
Sudha Raman, PhD Assistant Professor in Population Health Sciences Department of Population Health Sciences Duke University School of Medicine
Topic
Leveraging RWD in a Multinational Trial: Results from the Other eHARMONY (HARMONY Outcomes EHR Ancillary Study)
Keywords
Electronic health records; eHARMONY; Real-world data; DataMart; Common data model; Data sensitivity/specificity
Key Points
While the electronic health record (EHR) is a rich source of clinical data, the fitness of EHR data for use in high-quality clinical research has not been rigorously evaluated.
The HARMONY trial aimed to determine the effect of albiglutide, when added to standard blood glucose lowering therapies, on major cardiovascular events in patients with type 2 diabetes mellitus. eHARMONY was an ancillary study conducted alongside the HARMONY trial, with these objectives:
Understand how EHR data are used to facilitate trial recruitment and what the barriers are to that use
Evaluate the fitness of real-world data (RWD) data for use in populating baseline characteristics in the electronic case report form
Evaluate the fitness of RWD data for use in identifying clinical endpoints
In the eHARMONY study, assessing data quality and fitness of a site’s EHR data was often not possible. Among the lessons learned were:
Each strategy required ongoing feasibility assessment
Standalone clinical research sites had very little (extractable) EHR data about patients
Lab results and medications were either not extractable or not mapped to a useful terminology
Many sites did not participate because they knew they could not perform this work, and many sites that promised to do this work could not deliver
Discussion Themes
What structural and behavioral factors have you encountered? For example, a healthcare system might not provide a particular service, or a healthcare system provides the service but people might choose to receive it elsewhere.
What about the overall cost of the trial? Has anything changed over the last 5 years—or are we consigned to spend hundreds of millions on outcome trials?
To realize the potential of real-world data in clinical trials, be mindful of the actual context of the trial, and (1) keep it simple, (2) collect only the data you need for the question at hand, and (3) remember that clinical research is not the priority for healthcare systems.
It is also essential for studies to report what does not work.
We are pleased to announce our new collection of short educational videos that highlight advances in the use of electronic health records (EHRs) in pragmatic clinical trials.
The videos are drawn from our 2020 EHR Workshop Grand Rounds Series, “Advances at the Intersection of Digital Health, Electronic Health Records and Pragmatic Clinical Trials.” The series highlighted advances in digital health, new approaches and evolving standards for EHRs, and implications for researchers conducting pragmatic trials. Experts discuss the evolving regulatory context for EHRs, national policy priorities, and innovative uses of EHRs in several NIH Collaboratory Trials.
Video topics include:
Real-World Data and Real-World Evidence in Regulatory Decisions
Ahmed Al-Jaishi, PhD (candidate) Health Research Methodology McMaster University
Amit Garg, MD, PhD Professor, Department of Medicine Epidemiology & Biostatistics Western University, London, Canada Senior Core Scientist, Site Director, and Program Lead ICES Western Kidney Dialysis & Transplantation Research Program, London, Canada Nephrologist, London Health Sciences Centre Victoria Hospital, London, Canada
Merrick Zwarenstein, MBBCh, MSc, PhD Professor, Department of Family Medicine Epidemiology & Biostatistics Western University, London, Canada Senior Core Scientist ICES Western Primary Care & Health Systems Research Program, London, Canada
Topic
Pragmatic and Explanatory Attitudes to RCTs: Using the PRECIS-2 Tool to Describe the Design of the MyTEMP Trial
Keywords
Pragmatic trials; PRECIS-2; Canadian Institutes of Health Research (CIHR); Study design; External validity
Key Points
Randomized controlled trial (RCT) intentions (attitudes) can be described as: pragmatic intentions provide evidence for decision-makers to choose between interventions, whereas explanatory intentions test a hypothesis about a mechanism.
Pragmatic and explanatory trials are not a dichotomy; a good trial design matches the intention of the trial.
Trials can be designed with both internal validity and external validity.
Different trial intentions, design choices, conclusions, and recommendations lead to different usefulness for decision-making.
Discussion Themes
Can you comment on the retrospective use of PRECIS-2 to dichotomize trials as pragmatic or explanatory?
What suggestions do you have to improve the labeling of trials as explanatory versus pragmatic, since both types are randomized controlled trials (RCTs)?
Read more about the PRECIS-2 tool and the CONSORT statement for pragmatic trials.
AcademyHealth is accepting abstracts for the 14th Annual Conference on the Science of Dissemination and Implementation in Health until July 27, 2021. This year’s meeting will be held virtually from December 14 to 16.
