study design

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

May 7, 2021: Online Recruitment in the Era of COVID-19: Pitfalls and Progress (Megan L. Ranney, MD, MPH)

Posted on by Gina Uhlenbrauck

Speaker

Megan L. Ranney, MD, MPH, FACEP
Director, Brown-Lifespan Center for Digital Health
Warren Alpert Endowed Associate Professor of Emergency Medicine, Brown University
Associate Dean of Strategy and Innovation, School of Public Health, Brown University
Chief Research Officer, AFFIRM
Co-founder, GetUsPPE

Topic

Online Recruitment in the Era of COVID-19: Pitfalls and Progress

Keywords

COVID-19; Online trial recruitment; Clinical trials; Emergency medicine; Digital health technologies; Remote interventions; Electronic informed consent

Key Points

  • The Center for Digital Health at Brown University is a research and education hub that explores innovative solutions to urgent health challenges. The Center has supported studies involving the use of digital health technologies for recruiting participants and delivering behavioral health interventions.
  • Due to disruptions caused by the COVID-19 pandemic, many research studies pivoted from in-person contact toward the use of digital technologies such as smartphone apps and remote telehealth.
  • To advance clinical trials in a post-pandemic world, we will need to establish best practices for digital health technologies—and recognize when online recruitment is appropriate and when it is not. Hybrid recruitment models offer a solution.

Discussion Themes

It remains clear that the relationship between study staff and participants is essential to forming positive alliances and determines the likelihood of follow up.

For social media advertising, it’s possible that an IRB could approve a group of images, headlines, and content that study teams can combine in different ways to optimize the advertising over the course of a study.

The Pew Research Center provides recent data on which social media platforms are used most by Americans. Read more about digital health science at the Center for Digital Health.

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#pctGR, @Collaboratory1

April 30, 2021: ACTIV-6: COVID-19 Outpatient Randomized Trial to Evaluate Efficacy of Repurposed Medications (Susanna Naggie, MD, MHS; Elizabeth Shenkman, PhD)

Posted on by Gina Uhlenbrauck

Speakers

Susanna Naggie, MD, MHS
Associate Professor of Medicine
Duke Clinical Research Institute

Elizabeth Shenkman, PhD
Chair, Department of Health Outcomes and Biomedical Informatics
Co-Director, Clinical and Translational Science Institute (CTSI)
University of Florida

Topic

ACTIV-6: COVID-19 Outpatient Randomized Trial to Evaluate Efficacy of Repurposed Medications

Keywords

COVID-19; NIH ACTIV Initiative; Repurposed drugs; Vaccines; Therapeutic agents; Direct-to-participant trials; PCORnet

Key Points

  • Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) is a public-private partnership to develop a coordinated research strategy for prioritizing and speeding development of the most promising treatments and vaccines. The ACTIV initiative is coordinated by the Foundation for the National Institutes of Health.

  • ACTIV-6 asks: Are there medications currently approved for other conditions that improve symptoms in nonhospitalized patients with mild-to-moderate COVID-19 symptoms? The study aims to find out how to help patients feel better faster and how to prevent hospitalizations or death in newly diagnosed patients with mild or moderate COVID-19.

  • All study visits are conducted remotely: Participants use an online system to complete study surveys and report adverse events or changes in clinical status. Participants are assigned randomly to receive either a placebo or one of the treatments, which will be sent to them by mail. If deemed necessary by a study investigator, in-person or remote study visits are possible.

Discussion Themes

Vaccine hesitancy is still an issue, especially in rural areas; there will continue to be cases of COVID-19.

To ensure diversity in enrollment, the ACTIV-6 study takes a multipronged approach, including making it easy to participate without in-person appointments; partnering with community groups for broad outreach and messaging; and monitoring enrollment numbers closely.

Sites provide participant education and recruitment. The process is straightforward and appeals to both clinicians and patients. Each study site has a primary care physician as a clinical champion.

Read more about ACTIV-6, the NIH’s ACTIV initiative, and the ACTIV master protocols including ACTIV-6.

Tags

#pctGR, @Collaboratory1

April 16, 2021: Minnesota EHR Consortium COVID-19 Project: A Statewide Collaboration to Inform Vaccine Equity (Paul E. Drawz, MD, MHS, MS; Tyler Winkelman, MD, MSc)

Posted on by Gina Uhlenbrauck

Speakers

Paul E. Drawz, MD, MHS, MS
Associate Professor
Division of Renal Disease and Hypertension
University of Minnesota

Tyler N.A. Winkelman, MD, MSc
Co-Director, Health, Homelessness, and Criminal Justice Lab
Associate Director, Virtual Data Warehouse
Hennepin Healthcare Research Institute

Topic

Minnesota EHR Consortium COVID-19 Project: A Statewide Collaboration to Inform Vaccine Equity

Keywords

COVID-19; Electronic health records (EHRs); Data analysis; Research consortium; Healthcare systems; Population health; Distributed data network; Vaccine equity

Key Points

  • The EHR Consortium’s COVID-19 vaccine project aims to inform policy and practice through data-driven collaboration among members of Minnesota’s health care community.
  • The collaborative network can monitor population-level health metrics and analyze changes over time using aggregations of data to inform public health policy. Sources of data include EHRs, census data, state-wide electronic immunization records, and population data.
  • The COVID-19 vaccine dashboard is updated weekly and provides data at the ZIP level by age categories and race/ethnicity.
  • Minnesotans who have received a COVID-19 vaccine (any source) and had a visit at a consortium site in the last 10 years (~90 percent of the state population) are reflected in the dashboard.

Discussion Themes

How were you able to convene this consortium during a pandemic year?

Was your hashing algorithm home-grown or did you have an outside partner?

In the future, this infrastructure will be expanded to incorporate smaller health systems and additional content expertise around comorbidities, disease prevalence, and identification of disparities in near real-time.

Read more about the MN EHR Consortium at Hennepin Healthcare and the University of Minnesota Clinical & Translational Science Institute.

Tags

#pctGR, @Collaboratory1

April 9, 2021: Taking Research to the Participant: Experiences with TREAT NOW, a No-Touch COVID-19 Trial (Adit Ginde, MD, MPH)

Posted on by Gina Uhlenbrauck

Speaker

Adit Ginde, MD, MPH
Professor and Vice Chair for Research, Department of Emergency Medicine
Director of Clinical Research, Department of Anesthesiology
Director, Colorado CTSI Trial Innovation Network Hub
University of Colorado School of Medicine

Topic

Taking Research to the Participant: Experiences with TREAT NOW, a No-Touch COVID-19 Trial

Keywords

COVID-19; No-touch trial design; Antiviral therapy; Adaptive platform trial; Repurposed drugs; Patient-reported outcomes

Key Points

  • The TREAT NOW trial evaluated the effectiveness and safety of early treatment with antiviral agents (lopinavir/ritonavir) in outpatient adults with COVID-19 for preventing hospitalization and improving clinical outcomes.
  • The trial used an adaptive platform approach with the ability to add or remove agents, and focused on repurposed FDA-approved therapies that are rapidly scalable and easily deployed.
  • The no-touch design required that the entire trial be completed without having any physical interaction with the participant.
  • TREAT NOW shows that no-touch trials are not only feasible but also effective. However, considerable effort was needed to get the smart data systems right. The data system must accommodate many different levels of technical skill, different languages, and different modes of communication.

Discussion Themes

What is the role of a site in a no-touch trial?

What was the most effective recruitment strategy?

What is the demographic breakdown of your participants?

Read more about the TREAT NOW trial on ClinicalTrials.gov.

Tags

#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 19, 2021: HERO-Learning Together about Vaccines for SARS-CoV-2 (Emily O’Brien, PhD; Robert Califf, MD)

Posted on by Gina Uhlenbrauck

Speakers

Emily O’Brien, PhD, FAHA
Associate Professor
Duke Clinical Research Institute
Duke University School of Medicine
 
Robert M. Califf, MD, MACC
Head of Clinical Policy and Strategy
Verily Life Sciences and Google Health

Topic

HERO-Learning Together about Vaccines for SARS-CoV-2

Keywords

COVID-19; Vaccine confidence; Side effects; Postmarketing surveillance; Long-term vaccine safety; Virus variants; PCORI; HERO Registry

Key Points

  • In the United States to date, more than 100 million doses of COVID-19 vaccine have been administered. Yet there remains concern about the increase in variants of the coronavirus.
  • Postmarket evidence generation around COVID-19 vaccines is critically important to understanding the long-term safety of vaccines and building confidence around their use.
  • A “pod” is the group of people you live with or relate to as family and have regular household contact with at least once per week for the past 3 months.

Discussion Themes

What does it mean to be a “safe vaccine”?

We’re still learning about how families are navigating the psychosocial aspects of this pandemic.

Over time, manual processes will be replaced by algorithms and automated systems. But we need to develop digital technologies that support human interactions in health.

What will be the key issues around COVID-19 in 2022?

HERO-TOGETHER is a paid observational research study for people aged 18 and older working in healthcare who have received a COVID-19 vaccine. Eligible participants include anyone who works in a setting where people receive healthcare. Read more about the HERO Program and how to join the registry.

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#pctGR, #HEROTOGETHER, @Collaboratory1, @heroesresearch

March 12, 2021: Lessons Learned from the Gates MRI Virtual COVID-19 Trial (Mohamed Bassyouni, PharmD; Jintanat Ananworanich, MD, PhD)

Posted on by Gina Uhlenbrauck

Speakers

Mohamed Bassyouni, PharmD
Product Development Program Leader
Bill and Melinda Gates Medical Research Institute
Cambridge, MA
 
Jintanat Ananworanich, MD, PhD
Clinical Development Leader
Bill and Melinda Gates Medical Research Institute
Cambridge, MA

Topic

Lessons Learned from the Gates MRI Virtual COVID-19 Trial

Keywords

COVID-19; Virtual trial; Gates Medical Research Institute (MRI); Underserved populations; Health outcomes; Treatment safety and efficacy; Decentralized trial

Key Points

  • The goal of this study was to conduct a randomized controlled, adaptive platform trial to evaluate safety and efficacy of interventions for high-risk people with mild COVID-19 disease.
  • A key feature of the virtual trial was the development of a “COVID trial in a box.” This innovative method involved a single shipment of the study materials—including the study drug, lab sample kits, pulse oximeter, and PPE—directly to study participants’ homes.
  • The study evaluated multiple strategies for participant identification and outreach. Challenges included finding a better approach to engage minority communities; having better access for potential participants to be screened for COVID-19; increasing participation in the elderly population.

Discussion Themes

100% remote trials are possible and are especially crucial during a pandemic.

How did the study use social medial for virtual screening?

Did you do exit interviews with participants to get feedback on outreach and study design? 

Were alternatives to eConsent offered to patients who may have had technical difficulty with electronic apps or platforms?

Read more at the Gates Medical Research Institute website.

Tags

#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