randomized controlled trials

June 19, 2020: Living Textbook Grand Rounds Series: Part 4-Demystifying Biostatistical Concepts for Embedded Pragmatic Clinical Trials (Elizabeth Turner, PhD; Patrick Heagerty, PhD; David Murray, PhD)

Posted on by Gina Uhlenbrauck

Speakers

Elizabeth Turner, PhD
Associate Professor
Department of Biostatistics & Bioinformatics
Duke Global Health Institute
Duke University  

Patrick Heagerty, PhD
Professor Department of Biostatistics
University of Washington  

David Murray, PhD
Associate Director for Prevention
Director, Office of Disease Prevention National Institutes of Health

Topic

Demystifying Biostatistical Concepts for Embedded Pragmatic Clinical Trials

Keywords

Embedded PCTs; Biostatistics; Trial design; Cluster-randomized trial (CRT); Stepped-wedge; Intraclass correlation coefficient; NIH Collaboratory Trial; Sample size; Individually randomized group treatment

Key Points

  • Focus on the research question, because that will drive the design, and the design will drive the analysis.
  • Select design features with analysis in mind, and collaborate early with a statistician. Weigh statistical choices against the challenges of implementation.
  • If possible, choose individual randomization. However, sometimes there is a strong rationale for choosing cluster/group randomization. Clustering must be accounted for in both design and analysis for CRTs and individually randomized group treatment (IRGT) trials.
  • The intraclass correlation coefficient (ICC) is a common measure of outcome clustering. Estimating the ICC is needed for study planning and power.
  • Increasing the number of clusters has more impact on power than increasing the number of patients per cluster.

Discussion Themes

With the move to virtual healthcare, the boundaries between clinic-based clusters have become more fluid. What approaches should trials use to describe contamination and estimate the impact of contamination on outcomes?

Read more about ICC in a Living Textbook resource and visit the Training Resources page for practical help on how to plan and conduct ePCTs.

Learn more in the Living Textbook about considerations for trial design and analysis for ePCTs.

Visit the NIH Collaboratory’s Biostatistics and Study Design Core webpage for more resources around design and analysis issues in ePCTs.

The NIH hosts a Research Methods Resources website with materials on this topic.

Tags

#pctGR, @Collaboratory1

June 17, 2020: Living Textbook Grand Rounds Series Continues With “Demystifying Biostatistical Concepts”

Posted on by Damon Seils

Join us Friday, June 19, for “Demystifying Biostatistical Concepts for Embedded Pragmatic Clinical Trials,” the fourth session in our special 5-part Grand Rounds series focused on the Living Textbook. NIH Collaboratory investigators Drs. Liz Turner, Patrick Heagerty, and David Murray will discuss statistical design considerations, choosing the right design, and implications for the analysis. Topics covered will include:

  • RCTs, CRTs, and IRGTs: selecting the right trial design
  • Clustering and statistical power
  • Other analytical issues

See below for the full schedule of Living Textbook sessions and a special message from Dr. Kevin Weinfurt.

Living Textbook Grand Rounds Series
Date Title Speakers
January 31, 2020 Pragmatic Clinical Trials: How Do I Start?
  • Greg Simon, MD, MPH, Kaiser Permanente Washington Health Research Institute
  • Lesley H. Curtis, PhD, Duke University
February 28, 2020 Preparing for the Unknown: Conducting Pragmatic Research in Real-World Contexts
  • Jerry Jarvik, MD, MPH, University of Washington
  • Vince Mor, PhD, Brown University
  • Leah Tuzzio, MPH, Kaiser Permanente Washington Health Research Institute
March 27, 2020 Tips for Putting Together a Successful PCT Grand Application
  • Wendy Weber, ND, PhD, MPH, National Center for Complementary and Integrative Health
June 19, 2020 Demystifying Biostatistical Concepts for Embedded Pragmatic Clinical Trials
  • Liz Turner, PhD, Duke University
  • Patrick Heagerty, PhD, University of Washington
  • David M. Murray, PhD, National Institutes of Health
July 17, 2020 Choosing What to Measure and Making It Happen: Your Keys to Pragmatic Trial Success
  • Rachel Richesson, PhD, MPH, Duke University
  • Emily O’Brien, PhD, Duke University

 

May 28, 2020: New Updates to Design and Analysis Plan Chapters in the Living Textbook

Posted on by Damon Seils

The annual update of the Living Textbook has brought new content and organization to the Experimental Designs and Analysis Plan chapters. We invite you to explore these chapters and the external resources linked from the resources sidebar in each section.

The NIH Collaboratory Coordinating Center regularly refreshes content in the Living Textbook to improve the robust collection of resources it offers to the wider research community about how to plan and implement pragmatic clinical trials.

Sections of the Experimental Designs and Randomization Schemes chapter include:

  • Statistical Design Considerations
  • Cluster Randomized Trials
  • Randomization Methods
  • Choosing Between Cluster and Individual Randomization
  • Alternative Cluster Randomized Designs
  • Concealment and Blinding
  • Designing to Avoid Identification Bias
  • Additional Resources

Sections of the Analysis Plan chapter include:

  • Intraclass Correlation
  • Unequal Cluster Sizes
  • Accounting for Residual Confounding in the Analysis
  • Missing Data and Intention-to-Treat Analyses
  • EHR Data Extraction
  • Unanticipated Changes
  • Case Study: STOP CRC Trial

May 19, 2020: New Updates to What is a Pragmatic Clinical Trial Chapter in the Living Textbook

Posted on by Gina Uhlenbrauck

The NIH Collaboratory regularly refreshes content in the Living Textbook in order to offer a robust collection of resources to the wider research community about how to plan and implement a pragmatic clinical trial. We invite you to explore recent additions to the introductory chapter What Is a Pragmatic Clinical Trial?

Highlights include information on the broader embedded PCT (ePCT) ecosystem, an updated table describing the 19 NIH Collaboratory Trials, a new illustration of the PRECIS-2 continuum, webinars on how to start a PCT, and more.

“The Living Textbook reflects a collection of expert consensus regarding special considerations, standard approaches, and best practices in the design, conduct, and reporting of PCTs.” – Dr. Kevin Weinfurt, Editor-in-Chief of the Living Textbook

Sections in What is a Pragmatic Clinical Trial include:

  1. Why Are We Talking About Pragmatic Trials?
  2. The Embedded Pragmatic Clinical Trial Ecosystem
  3. Differentiating Between RCTs, PCTs, and Quality Improvement Activities
  4. Pragmatic Elements: An Introduction to PRECIS-2
  5. Key Considerations for PCTs
  6. Additional Resources

May 15, 2020: Optimized Learning While Doing: The REMAP-CAP Adaptive Platform Trial (Derek Angus, MD, MPH)

Posted on by Gina Uhlenbrauck

Speaker

Derek C. Angus, MD, MPH, FRCP
Distinguished Professor and Mitchell P. Fink Endowed Chair
Department of Critical Care Medicine
University of Pittsburgh and UPMC Health System

Topic

Optimized Learning While Doing: The REMAP-CAP Adaptive Platform Trial

Keywords

Adaptive study design; REMAP-CAP; Community-acquired pneumonia; Embedded research; Learning health system; Pandemic; Response-adaptive randomization; Global adaptive platform; COVID-19

Key Points

  • The Randomised, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) aims to determine and continuously update the optimal set of treatments for community-acquired pneumonia.
  • An important aspect of adaptive trial designs is that already accrued data are used to increase the likelihood that patients within the trial are randomized to treatments that are beneficial.
  • With the onset of the COVID-19 pandemic, the REMAP study made use of an adaptive sub-platform called REMAP-COVID, which is studying multiple questions around COVID treatment simultaneously.

Discussion Themes

The COVID-19 pandemic requires us to do two things at once: learn and do. An integrated approach finds the optimal balance to treat patients as well as possible and learn as fast as possible.

Adaptive randomization is potentially more comfortable for physicians, where patients are preferentially assigned to the best therapy over time.

Read more about REMAP-CAP and Dr. Angus’ research in Optimizing the Trade-off Between Learning and Doing in a Pandemic (JAMA, March 2020).

Tags

#pctGR, @Collaboratory1, @remap_cap

April 22, 2020: New Article Details the Design of ADAPTABLE, PCORnet’s First Pragmatic Trial

Posted on by Damon Seils

A new article in JAMA Cardiology discusses the design of ADAPTABLE, a pragmatic clinical trial (PCT) which strives to answer a three-decade-old question with great potential significance for public health. ADAPTABLE is the first PCT to use many of the data-driven and patient-centric capabilities of the National Patient-Centered Clinical Research Network (PCORnet).

Researchers in ADAPTABLE pursued the unanswered question of whether a low dose or high dose of aspirin is optimal for secondary prevention of atherosclerotic cardiovascular disease. Complexities of running a randomized clinical trial and the expenses associated with it have previously prevented researchers from answering this question.

The capabilities of PCORnet have aided in this research. Though not all randomized clinical trials can be designed as PCTs, ADAPTABLE demonstrates the possibility of incorporating pragmatic elements into future studies with the goal of producing real-world evidence.

A key objective of involving PCORnet in ADAPTABLE was the ability for large-scale recruitment (15,000 participants) using electronic health records and electronic informed consent. The PCORnet component permitted complete electronic participation, from randomization to data collection. Patients reported their own data during scheduled electronic follow-ups, which replaced conventional follow-up visits.

NIH Collaboratory Coordinating Center co–principal investigator Dr. Adrian Hernandez also serves as co–principal investigator of ADAPTABLE and contributed to the article.

See the accompanying editorial describing lessons learned from the design features of ADAPTABLE.

April 15, 2020: NIH Collaboratory COVID-19 Grand Rounds Series Continues With Discussion of HERO Program for Healthcare Workers

Posted on by Damon Seils

The NIH Collaboratory Coordinating Center is using its popular Grand Rounds platform to share late-breaking research and promote resources in support of clinical researchers affected by the COVID-19 public health emergency.

In this week’s COVID-19 Grand Rounds session, leaders of the Patient-Centered Outcomes Research Institute (PCORI) and investigators from the Healthcare Worker Exposure Response and Outcomes (HERO) registry and the HERO-HCQ randomized clinical trial will present “The HERO Program: PCORnet® at Work to Create a Healthcare Worker Community for Rapid Cycle Evidence.” The Grand Rounds session will be held on Friday, April 17, at 1:00 pm eastern. Join the online meeting.

Previous COVID-19 Grand Rounds:

Recent news announcements:

We will continue to share new research, resources, and guidance as they become available.

April 10, 2020: Hydroxychloroquine for the Early Treatment of COVID-19 in Hospitalized Adults: A Multicenter Randomized Clinical Trial (Sean Collins, MD, MSc)

Posted on by Gina Uhlenbrauck

Speaker

Sean Collins, MD, MSc
Professor and Executive Vice Chair
Department of Emergency Medicine
Director, Center for Emergency Care Research and Innovation
Vanderbilt University Medical Center

Topic

Hydroxychloroquine for the Early Treatment of COVID-19 in Hospitalized Adults: A Multicenter Randomized Clinical Trial

Keywords

Coronavirus; Virus pandemic; COVID-19; Randomized controlled trial; Acute respiratory distress syndrome (ARDS); Hydroxychloroquine; FDA; Emergency Use Authorization; ORCHID study

Key Points

  • Hydroxychloroquine is a biologically plausible agent for early treatment of acute respiratory distress syndrome in patients with COVID-19, but its effects remain to be evaluated in a high-quality, multicenter, blinded, placebo-controlled trial.
  • In an Emergency Use Authorization, the FDA has encouraged the conduct and participation in randomized controlled clinical trials that may produce evidence concerning the effectiveness of hydroxychloroquine in treating patients with COVID-19.
  • Trial results of the effects of this agent will be informative, whether showing benefit or harm.

Discussion Themes

The study team for this trial determined that one-to-one randomization would yield the best data quickly.

Efficacy and safety of hydroxychloroquine must be closely monitored in a health setting.

This is not the only study of chloroquine going on around the world; is there any collaboration with other studies?

Because of the urgency of the pandemic, people are collaborating on a level never seen before. We have a common goal and must maintain momentum through accelerating clinical trials with large teams of parallel studies.

Read more about this COVID-19 study at NCT04332991.

Tags
#pctGR, @Collaboratory1

March 30, 2020: New Living Textbook Chapter Describes Ways to Monitor Intervention Fidelity and Adaptations During the Conduct of ePCTs

Posted on by Gina Uhlenbrauck

The new Monitoring Intervention Fidelity and Adaptations chapter of the Living Textbook was developed to introduce how to evaluate changes that may be encountered while conducting an embedded pragmatic clinical trial (ePCT). For example, a health system might experience competing clinical initiatives; turnover in leadership, clinicians, or staff; changes in technologies; new clinical practice guidelines; or regulatory changes.

The chapter offers strategies for study teams to anticipate, monitor, and document adaptations to the intervention in order to support study analysis and set the stage for dissemination and implementation of successful interventions in other healthcare settings. The chapter was developed by experts from the Collaboratory’s Health Care Systems Interactions Core, along with principal investigators conducting ePCT Demonstration Projects.

Topics include:

  • Anticipating changes that might impact intervention fidelity
  • Frameworks to assist in monitoring fidelity and adaptations
  • Strategies and case examples from the NIH Collaboratory Demonstration Projects
  • Pointers to additional resources

We encourage you to explore this new content.

 

March 20, 2020: Clinical Trials in the Time of COVID-19 (Susanna Naggie, MD; Adrian Hernandez, MD, MHS; Eric Perakslis, PhD)

Posted on by Gina Uhlenbrauck

Speakers

Susanna Naggie, MD
Associate Dean for Clinical Research Initiatives and Regulatory Affairs
Duke University School of Medicine

Adrian F. Hernandez, MD, MHS
Professor of Medicine
Vice Dean for Clinical Research
Duke University School of Medicine

Eric Perakslis, PhD
Rubenstein Fellow
Duke University

Topic

Clinical Trials in the Time of COVID-19

Keywords

Infectious disease; Coronavirus; Pandemic response; COVID-19; Population health; Clinical trials; Human subject protections; Contingency measures; Vaccine; Contact tracing

Key Points

Discussion Themes

Do you anticipate that statisticians will need to account for period effect in later analysis of data (pre/post COVID-19)?

Are there lessons learned from the last epidemics, for example H1N1 or Ebola? How can we deal with global pandemics in the future?

What about clinical trials in the elderly population, given that they are the most vulnerable to the coronavirus and may not be as good with technology as younger participants?

Would it be possible to set up a multisite telehealth-based outbreak learning health unit?

Recent news announcements are available at NIH Announces Guidance for Clinical Trials Affected by COVID-19 Emergency and NIH Shares COVID-19 Guidance and Resources for Applicants and Recipients.

Johns Hopkins University maintains a live website of Coronavirus COVID-19 Global Cases.

Tags
#pctGR, @Collaboratory1, @texhern, @snaggie1, @DukeForge, @eperakslis