research methods

June 24, 2021: New Article Offers Guidance on Accounting for Quality Improvement Activities During Embedded Pragmatic Trials

Posted on by Karen Staman

Cover of the journal HealthcareIn 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.

For more, see the Living Textbook Chapters on Advice from Health Care System Leadership,  Building Partnerships to Ensure a Successful Trial, and Monitoring Intervention Fidelity and Adaptations.

May 21, 2021: The PRINCIPLE Adaptive Platform Trial for Community Treatment of COVID-19: Innovation in Trial Design and Delivery (Chris Butler, MD; Ben Saville, PhD)

Posted on by Damon Seils

Speakers

Chris Butler, MD
Nuffield Department of Primary Care Health Sciences
University of Oxford

Ben Saville, PhD
Berry Consultants

Topic

The PRINCIPLE Adaptive Platform Trial for Community Treatment of COVID-19: Innovation in Trial Design and Delivery

Keywords

COVID-19; Adaptive platform trial; PRINCIPLE; Master protocols; Direct-to-participant trial; Repurposed drugs

Key Points

  • 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.

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#pctGR, @Collaboratory1

May 14, 2021: Keynote Session: Diverse Representation Among Clinical Trial Participants: Why It Is Important and How Can We Improve (Clyde W. Yancy, MD, MSc)

Posted on by Gina Uhlenbrauck

Speaker

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.

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#pctGR, @Collaboratory1

April 2, 2021: Lessons from COVID-19: The First Year of the REMAP-CAP Global Adaptive Platform Trial (Derek Angus, MD, MPH)

Posted on by Gina Uhlenbrauck

Speaker

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.

Tags

#pctGR, @Collaboratory1

March 5, 2021: Data and Safety Monitoring Boards for Trials of COVID-19 Vaccines: The Challenges (Susan S. Ellenberg, PhD)

Posted on by Gina Uhlenbrauck

Speaker

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.

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#pctGR, @Collaboratory1

February 26, 2021: Calibrating Real-World Evidence Against RCT Evidence: Early Learnings from RCT-DUPLICATE (Sebastian Schneeweiss, MD, ScD)

Posted on by Gina Uhlenbrauck

Speaker

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

Keywords

Real-world evidence (RWE); Randomized controlled trials (RCTs); Epidemiology; Emulation; Fit-for-purpose data

Key Points

  • 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.

Read more about RCT-DUPLICATE in Circulation.

Tags

#pctGR, @Collaboratory1

February 12, 2021: Leveraging RWD in a Multinational Trial: Results from the Other eHARMONY [HARMONY Outcomes EHR Ancillary Study] (Lesley Curtis, PhD, Bradley Hammill, PhD, Sudha Raman, PhD)

Posted on by Gina Uhlenbrauck

Speakers

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.

Read more about how real-world data (RWD) and real-world evidence (RWE) are playing an increasing role in health care decisions.

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#pctGR, @Collaboratory1

January 5, 2021: New Video Collection Highlights Advances in Electronic Health Records for Pragmatic Research

Posted on by Damon Seils

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:

Visit the EHR Workshop Video Modules page for access to all of the new videos.

November 13, 2020: Pragmatic and Explanatory Attitudes to RCTs: Using the PRECIS-2 Tool to Describe the Design of the MyTEMP Trial (Ahmed Al-Jaishi, PhD; Amit Garg, MD, PhD, Merrick Zwarenstein, MBBCh, MSc, PhD)

Posted on by Gina Uhlenbrauck

Speakers

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.

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#pctGR, @Collaboratory1

October 23, 2020: Outpatient Clinical Decision Support – An Evidence-Based Implementation Framework (Patrick O’Connor, MD, MA, MPH; JoAnn Sperl-Hillen, MD)

Posted on by Gina Uhlenbrauck

Speakers

Patrick O’Connor, MD, MA, MPH
Senior Clinical Investigator
HealthPartners Institute

JoAnn Sperl-Hillen, MD
Senior Clinical Investigator
HealthPartners Institute

Topic

Outpatient Clinical Decision Support – An Evidence-Based Implementation Framework

Keywords

Clinical decision support; Electronic health record (EHR); Automated tools; Web applications; Clinical informatics

Key Points

  • A well-designed clinical decision support (CDS) system should fire only when there is a potential large benefit, such as a cardiovascular benefit for patients with a reversible risk. The CDS trigger should be patient-centric, and the system should save clinician time and improve the quality of care.

  • The CDS in question was designed for use in cardiovascular (CV) disease to:

    • Identify and target individuals with the greatest potential for a CV benefit and prioritize CV risk factors based on potential benefit.

    • Display personalized treatment options (eg, medication intensification, behavioral/lifestyle change, safety alerts, referrals, and testing due).

    • Provide tools to both the patient and clinician to support patient engagement and shared decision-making.

Discussion Themes

How are the interventions prioritized in the CDS system? What about decision-making across other clinical domains?

What do you see as the drivers of uptake and adoption of CDS with triggers compared with telehealth?

What clinic challenges did you encounter after the onset of COVID-19?

Read more in Clinical Decision Support Directed to Primary Care Patients and Providers Reduces Cardiovascular Risk: A Randomized Trial (J Am Med Inform Assoc, 2018) and NCT01420016 (ClinicalTrials.gov).

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#pctGR, @Collaboratory1