October 12, 2023: GRACE Team Shares Lessons About Monitoring Signals of Suicidality in Pragmatic Clinical Trials

In a new article published this week in Contemporary Clinical Trials Communications, the GRACE DNIH Collaboratory Trial team recommends that suicidality should be monitored in pragmatic clinical trials that measure depression as an outcome. The work builds on their experience conducting research involving patients with sickle cell disease and on previous work from the NIH Pragmatic Trials Collaboratory’s Ethics and Regulatory Core.

The authors offer 7 recommendations to address ethical considerations in the development of protocols, procedures, and monitoring activities related to suicidality in depressed patients in a pragmatic clinical trial.

Recommendations:

  • Understand our responsibility to act
  • Define triggers for action
  • Examine responsibilities for action
  • Protect patient autonomy and privacy
  • Identify indirect and collateral participants
  • Mitigate the risk of bias
  • Integrate responses within the clinical practice and understand the sociotechnical considerations.

Severe depression symptoms such as suicidal ideation can be assessed in patients using the PHQ-9, a validated self-report instrument used to score depression severity by inquiring about the  presence and severity of depression, passive thoughts of death, and active ideas of self-harm.

For more, read the full article or the article Responding to Signals of Mental and Behavioral Health Risk in PCTs from the Ethics and Regulatory Core.

The GRACE is supported by the NIH through the NIH HEAL Initiative under an award administered by the National Center for Complementary and Integrative Health. Learn more about the GRACE trial.

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

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)

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.

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#pctGR, @Collaboratory1

April 23, 2021: COVID Clinical Trials: The Intermountain Healthcare Experience (Samuel M. Brown, MD, MS)

Speaker

Samuel M. Brown, MD, MS
Associate Professor and Director of Pulmonary/Critical Care Research
Intermountain Healthcare
Associate Professor, University of Utah

Topic

COVID Clinical Trials: The Intermountain Healthcare Experience

Keywords

COVID-19; Public health; Integrated health system; COVID-19 treatment trials

Key Points

  • Intermountain Healthcare is a nonprofit, community-based healthcare system that maintains an academic referral center and several hospitals in Utah.
  • During the pandemic, the health system was able to integrate COVID-19 research with urgent clinical, operational, and public health needs. The health system currently supports 15 randomized clinical trials in COVID-19 research, investigating immunologic and virologic therapies.
  • Collaboration and communication across divisions were essential elements to the successes achieved.
  • Among the challenges of conducting the COVID-19 trials, there remains a wish for a comprehensive risk management solution and regulatory reform.

Discussion Themes

Could we establish a robust program that provides better training and pay for study coordinators? These staff have direct contact with participants for recruitment and retention and can make or break a trial.

What aspects of institutional culture contributed to the success of conducting these trials?

What is needed is a clinical research ecosystem that appropriately balances regulatory oversight with the agility to answer urgent health questions.

Read more about Intermountain Healthcare’s experiences with COVID-19 clinical trials in these recent publications:

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#pctGR, @Collaboratory1

April 22, 2021: Materials From the NIH Collaboratory Steering Committee’s Virtual Meeting Now Available

On April 14 and 15, 2021, more than 100 participants joined the online Steering Committee meeting to discuss important considerations for Collaboratory trials and the embedded pragmatic clinical trial ecosystem at large, including adaptations made due to COVID-19, data sharing models and experiences, barriers encountered, and lessons learned. All presentations are available for download.

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

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)

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.

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#pctGR, @Collaboratory1

March 26, 2021: The Path to Preventive Genomics (Robert C. Green, MD, MPH)

Speaker

Robert C. Green, MD, MPH
Professor of Medicine (Genetics), Harvard Medical School
Director, Genomes2People Research Program and Preventive Genomics Clinic
Mass General Brigham, Ariadne Labs, Broad Institute

Topic

The Path to Preventive Genomics

Keywords

Preventive genomics; Whole genome sequencing; Return of results; Risk stratification; Precision medicine

Key Points

  • The goal of the Genomes2People research program is to bring genomics into evidence-based patient care. The program conducts empirical research in translating genomics into health, including the first rigorous trials to provide comprehensive genome sequencing to adults and newborn infants.
  • Twenty percent of healthy people are carrying a monogenic disease risk variant. The number of people carrying variants for monogenic diseases depends on how many genes are analyzed.
  • Polygenic risk is the chance of developing certain health conditions based on a large number of genetic variants across the genome.

Discussion Themes

People are interested in medical information about themselves. It’s up to the healthcare system and physicians to create nuanced communication about genetic information that helps people understand its role in health.

Is there a diversity of families seeking out genomic screening services?

Should genetic variants of unknown significance (VUS) be reported to the individual?

Read more at Genomes2People and Brigham Preventive Genomics Clinic.

Tags

#pctGR, @Collaboratory1, @genomes2people

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

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.

Tags

#pctGR, #HEROTOGETHER, @Collaboratory1, @heroesresearch

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

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.

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#pctGR, @Collaboratory1