clinical trials

Grand Rounds September 19, 2025: Hurdles for the Delivery of Clinical Trials: Insights From the REMAP-CAP Trial in Europe (Denise van Hout, MD, PhD)

Posted on by terren.green@duke.edu

Speaker

Denise van Hout, MD, PhD
Postdoctoral Researcher
Julius Center for Health Sciences and Primary Care
University Medical Center Utrecht, the Netherlands

Keywords

Adaptive platform trial, Regulatory efficiency, REMAP-CAP, Study design, Study startup.

Key Points

  • Randomised Embedded Multifactorial Adaptive Platform trial for Community-Acquired Pneumonia (REMAP-CAP) began in 2016 as a data driven analysis of ethical, administrative, and logistical and ethical (EARL) delays in clinical trials studying respiratory infections. The goal was embedded trials that are flexible, efficient, and agile to provide clinicians with high-quality evidence to make the best treatment decisions.
  • REMAP-CAP is a global multifactorial adaptive platform trial with a master protocol that can investigate multiple interventions in different treatment domains for a single disease.
  • Over 8000 patients in REMAP-CAP were randomized to 44 interventions in 16 different treatment domains between January 2019 and June 2023. Patients could be randomized to more than 1 domain resulting in 15656 randomizations. Enrollment increased during the COVID-19 pandemic.
  • Dr. van Hout believes that to improve clinical trials, we should treat the challenges as a scientific problem and solve them with the same rigor.
  • Regulatory requirements and informed consent regulations differed among sites causing confusion for the researchers about what documents should be submitted with the contract and protocol in each country. Drug labeling requirements in some countries also slowed protocol approval. EARL processes also slowed trial initiation and patient enrollment.
  • It was clear that overall enrollment in the UK outpaced the other 257 sites worldwide. The UK had a shorter period of time to a fully signed study contract and protocol approval compared with sites in other countries (5 days in the UK compared with 183 days in non-UK countries). This quicker time to signed contract was accomplished by either accepting the contract as-is or rejecting the contract – without negotiating small details. The UK was also 3 months faster than non-UK countries at enrolling the first patient after study approval (1 month vs 4 months, respectively) leading to more enrollment and more research questions answered.
  • In January of 2022 the EU centralized regulatory submission to a single portal (CTIS) to ease and speed the process of starting a new trial.

Discussion Themes

Adaptive platform trials were uncommon before the COVID-19 pandemic, but their value became clear during the pandemic. After the pandemic, REMAP-CAP focuses on different treatment domains for pneumonia. Maintaining the infrastructure for an adaptive platform trial is difficult if there is not a clear need such as there was during the COVID-19 pandemic.

Centralizing approval for trials under one government body could speed the approval process for studies. During times of high need, prioritizing one or two good trials over a lot of smaller trials can also help speed the process.

 

Learn more about REMAP-CAP at https://www.remapcap.eu/

Grand Rounds May 16, 2025: Pivoting Clinical Trials Into a New and Evolving World (Jeffrey A. Spaeder, MD; Adrian F. Hernandez, MD, MHS)

Posted on by Elizabeth Mccamic

Speakers

Jeffrey A. Spaeder, MD
Chief Medical and Scientific Officer
Senior Vice President
IQVIA

Adrian F. Hernandez, MD, MHS
Executive Director
Duke Clinical Research Institute
Vice Dean
Duke University School of Medicine

Keywords

Clinical Research; Clinical Trials; Industry Trials; Accelerating Research

Key Points

  • The U.S. lags behind in recruitment for cardiology trials. Even though the U.S. has the most sites, significantly fewer patients are enrolled. These trends suggest underlying legal, regulatory, and cost-related barriers, highlighting the need for improved clinical trial infrastructure.
  • Additionally, teams are growing, trust in science in the U.S. is low, and some health trends, such as obesity, hypertension, and diabetes, are going the wrong way. The U.S. leads avoidable deaths per 100,000 and could fall further behind, all while health care costs are rising.
  • If you are looking at the value of healthcare that is delivered in the U.S., we pay more than other countries but have worse outcomes. Healthcare expenses account for about 28% of the U.S. Federal budget. More than 90% of the volume of prescription drugs are generic with the exception of immunology, obesity, and diabetes. Retail net pricing of prescription drugs in the U.S. accounts for only 14% of all healthcare expenditures. These factors may lead policymakers to see an imbalance of expense to outcome.
  • This means for clinical trials there is an increased focus of using real-world data to make informed decisions, shorten timelines, and inform efficacy and safety. It will also be important to make sure endpoints are clinically relevant and more of an emphasis on strategy-focused research. There may also be more of an emphasis on improving outcomes from a lens of prevention
  • In industry, biopharma funding levels are increasing, with an emphasis on later-phase assets, and funding trends have returned to pre-COVID-19 levels. An increasing proportion of studies are initiated by emerging bio-pharma (EBP) sponsors. While overall measures of complexity has increased modestly, sites have experienced a greater increase – and so have study participants.
  • If there is a desire to increase industry-sponsored or other types of studies at academic medical centers, contracting timelines must be reduced, intellectual property causes significant churn with little value, IRB staffing and responsiveness is critical, cost and efficiency need to be appropriate value for expense, and principle investigators need to have actual availability for study activities.

Discussion Themes

-The U.S. conducts more clinical trials on rare diseases than other countries. Does that impact the numbers? The data from this presentation was from cardiovascular trials. The data was from common chronic cardiovascular diseases. The U.S. is an attractive place to conduct studies because the FDA regulatory timelines are predictable and fast, and the U.S. market is attractive, but enrollment per site is generally lower than it is elsewhere.

-How has IQVIA looked at drivers of cost and efficiency? Cost per patient has increased, driven by the complexity of studies and how imaging and other tools get built into studies. Investigators are trying to make studies more patient-centric, collecting data remotely, making visits fewer. There has also been an increased duration of studies, which is more costly. Time has real cost implications for sponsors.

-Is decentralization of trials a solution? It can be – hybridization can be helpful. How can you meet the patient where they are. You need clinician engagement but there are a lot of things that happen from beginning to end that could be decentralized. It has to be used selectively in the right situation.

-Is a centralized IRB a solution? They have real value if they have expertise and fast turnaround time – if they are credible, rigorous, and have experienced staff. In some situations, studies use a centralized IRB and then go through an institutional IRB as well.

May 12, 2025: Clinical Trials in a New and Evolving World, in This Week’s PCT Grand Rounds

Posted on by Damon Seils

Headshots of Dr. Jeffrey Spaeder and Dr. Adrian HernandezIn this Friday’s Rethinking Clinical Trials Grand Rounds, Jeffrey Spaeder and Adrian Hernandez will present “Pivoting Clinical Trials Into a New and Evolving World.”

The Grand Rounds session will be held on Friday, May 16, 2025, at 1:00 pm eastern.

Spaeder is the chief medical and scientific officer at IQVIA. Hernandez, who serves as co–principal investigator of the NIH Pragmatic Trials Collaboratory Coordinating Center, is a professor of medicine and vice dean in the Duke University School of Medicine and executive director of the Duke Clinical Research Institute.

Join the online meeting.

April 17, 2025: Researchers Illustrate Potential for Observational Studies of Real-World Data to Emulate Randomized Trials

Posted on by Damon Seils

Headshots of Dr. Xiaojuan Li and Dr. Sonal SinghResearchers applied the “target trial emulation framework” to highlight important design considerations for observational studies that use real-world data to emulate randomized clinical trials.

The work, which was supported by the NIH Pragmatic Trials Collaboratory’s Distributed Research Network and by a grant from the National Institute on Aging, was published this week in Alzheimer’s & Dementia: Translational Research & Clinical Interventions.

The US Food and Drug Administration has approved anti-amyloid beta monoclonal antibodies for the treatment of patients with early Alzheimer disease. However, the findings of the randomized trials that supported these approvals may have limited generalizability to clinical practice due to the trials’ strict eligibility criteria, limited treatment and follow-up periods, and close monitoring. Thus, little is known about the safety of anti-amyloid therapies in real-world settings.

Existing real-world data, such as information available in electronic health records and administrative claims databases, can support studies of safety and utilization outcomes. The target trial emulation framework can guide the design of such studies while minimizing the forms of bias commonly encountered in observational research.

Using the anti-amyloid therapy lecanemab as an example, the researchers described the key design and analytical considerations for observational studies intended to emulate randomized trials.

Read the full report.

Authors of the article include Xiaojuan Li, Bahareh Rasouli, Jennifer Lyons, Noelle Cocoros, and Richard Platt of Harvard Medical School and the Harvard Pilgrim Health Care Institute; and Sonal Singh, Ivan Abi-Elias, and Jerry Gurwitz of UMass Chan Medical School.

Learn more about the NIH Collaboratory’s Distributed Research Network.

March 19, 2025: Use of Generative AI in Clinical Trials, in This Week’s PCT Grand Rounds

Posted on by Damon Seils
Headshot of Dr. Alexander "AJ" Blood
Dr. Alexander “AJ” Blood

In this Friday’s PCT Grand Rounds, Alexander J. “AJ” Blood of Harvard Medical School and Brigham and Women’s Hospital will present “Generative Artificial Intelligence in Clinical Trials: A Driver of Efficiency and Democratization of Care.”

The Grand Rounds session will be held on Friday, March 21, 2025, at 1:00 pm eastern.

Blood is an instructor of medicine and associate director of the Accelerator for Clinical Transformation Research Group at Harvard Medical School and a cardiologist and intensivist at Brigham and Women’s Hospital.

Join the online meeting.

January 15, 2025: Designing for Diversity, in This Week’s PCT Grand Rounds

Posted on by Damon Seils
Headshot of Dr. Christopher Lindsell
Dr. Christopher Lindsell

In this Friday’s PCT Grand Rounds, Chris Lindsell of Duke University will present “Design for Diversity.”

The Grand Rounds session will be held on Friday, January 17, 2025, at 1:00 pm eastern.

Lindsell is professor and cochief of biostatistics and bioinformatics, director of data science and biostatistics at the Duke Clinical Research Institute, and director of biostatistics and bioinformatics at the Duke Clinical and Translational Science Institute—all at Duke University.

Join the online meeting.

December 3, 2024: Sharing Results With Research Participants Raises Special Considerations in Pragmatic Trials

Posted on by Damon Seils

Cover image of the journal Clinical TrialsIn a new report from the NIH Pragmatic Trials Collaboratory, a team of bioethicists explores the ethical obligation to share aggregate results from pragmatic clinical trials with research participants. They conclude with recommendations for how to meet this obligation.

The article was published online ahead of print in Clinical Trials.

There is growing appreciation of the importance of sharing aggregate results of clinical trials with research participants. However, this practice has not been examined in the context of pragmatic clinical trials, which have special features that may complicate the ethics and logistics of sharing aggregate results.

The report’s authors summarize the ethical arguments for sharing aggregate results and describe the features of pragmatic trials that may raise logistical and other barriers to disclosure. They also discuss the important role healthcare system partners play in sharing results from pragmatic trials.

The authors offer the following recommendations:

  • Sharing aggregate results with research participants should be the default, and decisions not to share should be justified
  • Planning for sharing aggregate results should begin early in the planning of the trial
  • The healthcare care systems in which the trial is embedded should be key partners in decisions about what and how to share
  • Proactive sharing of results from a pragmatic trial that was conducted under a waiver or alteration of consent, including an explanation for why consent was not obtained in the study, can promote trust in the investigators and their healthcare system partners

Read the full report.

The article was coauthored by members of the NIH Pragmatic Trials Collaboratory’s Ethics and Regulatory Core, including Stephanie Morain, Abigail Brickler, Joseph Ali, Caleigh Propes, and Kayla Mehl of Johns Hopkins University; Pearl O’Rourke, formerly of Partners HealthCare; Kayte Spector-Bagdady of the University of Michigan; Benjamin Wilfond of the Seattle Children’s Hospital; Vasiliki Rahimzadeh of the Baylor College of Medicine; and David Wendler of the NIH Clinical Center.

September 11, 2024: HARMONIE and a New Approach to Commercial Clinical Trials, in This Week’s PCT Grand Rounds

Posted on by Damon Seils
Headshot of Professor Saul Faust
Professor Saul Faust

In this Friday’s PCT Grand Rounds, Saul Faust of the University of Southampton will present “The HARMONIE Trial: Reimagining How to Design and Deliver Contract Commercial Clinical Trials.”

The Grand Rounds session will be held on Friday, September 13, 2024, at 1:00 pm eastern.

The HARMONIE trial was a pragmatic trial of the effect of nirsevimab on hospitalizations for respiratory syncytial virus–associated lower respiratory tract infection when administered in healthy infants in France, Germany, and the United Kingdom.

Faust is a professor of pediatric immunology and infectious diseases at the University of Southampton, the director of the National Institute for Health Research (NIHR) Southampton Clinical Research Facility, the clinical director of the Wessex Local Clinical Research Network, and a NIHR senior investigator.

Join the online meeting.

July 10, 2024: Asking Different Causal Questions in Randomized Trials, in This Week’s PCT Grand Rounds

Posted on by Damon Seils
Headshot of Dr. Miguel Hernán
Dr. Miguel Hernán

In this Friday’s PCT Grand Rounds, Miguel Hernán of Harvard University will present “Causal Estimands: Should We Ask Different Causal Questions in Randomized Trials and in the Observational Studies That Emulate Them?”

The Grand Rounds session will be held on Friday, July 12, 2024, at 1:00 pm eastern.

Hernán is the Kolokotrones Professor of Biostatistics and Epidemiology and the director of the CAUSALab at Harvard T.H. Chan School of Public Health. Researchers at the CAUSALab generate, analyze, and interpret data to support decision-makers in making better decisions about what works in medicine, public health, and policy.

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March 7, 2024: New Report Sets Out Posttrial Responsibilities in Pragmatic Clinical Trials

Posted on by Damon Seils
Headshot of Dr. Stepanie Morain
Dr. Stephanie Morain

In a new report from the NIH Pragmatic Trials Collaboratory, a team of bioethicists and implementation scientists argue for a “presumptive default” that the results of pragmatic clinical trials should be incorporated into healthcare delivery processes. This responsibility arises from a key rationale for conducting pragmatic trials: that they can facilitate uptake of their results by relevant decision-makers.

The open-access article was published this week in Learning Health Systems.

Much of the literature on posttrial responsibilities offers guidance on what is owed to research participants and broader communities at the conclusion of traditional explanatory clinical trials. Similar guidance is lacking for pragmatic trials.

The NIH Collaboratory researchers, led by Stephanie Morain of Johns Hopkins University, explore the distinct considerations that shape posttrial responsibilities in pragmatic trials. These include the responsibilities of the healthcare systems in which these trials are embedded, and decisions about implementation of interventions that show meaningful benefit after their integration into usual care settings, as well as deimplementation of those that do not.

Fulfilling this responsibility will require prospective planning by researchers, healthcare delivery system leaders, institutional review boards, and sponsors, so as to ensure that the knowledge gained from [pragmatic trials] does, in fact, influence real-world practice.

The article was coauthored by members of the NIH Collaboratory’s Ethics and Regulatory Core and Implementation Science Core, including Pearl O’Rourke, formerly of Partners HealthCare; Joseph Ali and Jeremy Sugarman of Johns Hopkins University; Vasiliki Rahimzadeh of the Baylor College of Medicine; and Devon Check and Hayden Bosworth of Duke University.

Read the full article.