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.
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.
In this Friday's PCT Grand Rounds, Rui Wang of Harvard Medical School will offer the final session in our special series, Advances in the Design and Analysis of Pragmatic Clinical Trials, with "Methods for Handling Missing Data in Cluster Randomized Trials." The session will be held on Friday, January 5, at 1:00 pm eastern.
Wang is an associate professor of population medicine and the director of the Division of Biostatistics in the Department of Population Medicine at Harvard Medical School and the Harvard Pilgrim Health Care Institute. She is also an associate professor in the Department of Biostatistics at the Harvard T.H. Chan School of Public Health. She is a longtime member of the NIH Pragmatic Trials Collaboratory's Biostatistics and Study Design Core Working Group.
This session's moderator, Fan Li, is an assistant professor of biostatistics at the Yale School of Public Health.
This special Grand Rounds series includes moderated webinar discussions that bring together biostatisticians, clinical trials methodologists, and investigators to discuss challenges and share lessons learned in the design, implementation, and analysis of pragmatic trials. Download the series flyer and see the full schedule below, including archived webinar recordings and slides from previous sessions.
The Grand Rounds session will be held on Friday, December 15, 2023, at 1:00 pm eastern.
Mehran is a professor of medicine and the director of interventional cardiovascular research and clinical trials at the Zena and Michael A. Wiener Cardiovascular Institute at the Mount Sinai School of Medicine.
The Grand Rounds session will be held on Friday, October 27, 2023, at 1:00 pm eastern.
The PaxLC Trial is a decentralized study of Paxlovid in adult participants with long COVID. Krumholz, the principal investigator for the trial, is the Harold H. Hines, Jr Professor of Medicine at Yale University and the director of the Yale-New Haven Hospital Center for Outcomes Research and Evaluation.
The Grand Rounds session will be held on Friday, August 18, 2023, at 1:00 pm eastern.
Landry is a professor of medicine and epidemiology at Oxford Population Health and deputy director of the University of Oxford’s Big Data Institute. ElZarrad is the director of the Office of Medical Policy in the FDA’s Center for Drug Evaluation and Research. Hernandez is a professor of medicine and vice dean of the Duke University School of Medicine and director of the Duke Clinical Research Institute, where he serves as co–principal investigator of the NIH Pragmatic Trials Collaboratory Coordinating Center.
Craig Lipset, MPH Co-Chair, Decentralized Trials & Research Alliance
Keywords
Decentralized; Guidance; FDA; Clinical trials
Key Points
Decentralized clinical trials (DCTs) are regular clinical trials in which all activities take place at locations other than traditional trial sites. Over the past several years, a variety of factors have accelerated the need for decentralized trials, including the push to make trials more accessible, the increased speed of science, the possibility of environmentally conscious trials, and the need to be flexible in a rapidly changing world.
During the COVID-19 pandemic, several regulatory authorities around the world introduced guidance on DCTs. There has been a growing sense of hesitancy about whether regulators will remain equally receptive to these decentralized methods when the pandemic recedes. The Food and Drug Administration (FDA) issued a draft guidance in May 2023 that provided guidance about the conduct of decentralized clinical trials. This guidance and others in development in other markets act as an important countermeasure to ensuring sustained adoption and implementation of DCTs.
The FDA draft guidance includes guidance around rules and expectations for topics, including patient safety and data integrity, location stipulations, rules for health care providers, telehealth versus in-person protocol, digital health technology, trial operations, management and supervision, consent, and investigational product (IP) administration. Additional considerations are needed for the data management plan, monitoring plan, safety plan, task log, and case report forms in the FDA draft guidance.
The European Medicines Agency (EMA) released a separate guidance around DCTs in December 2022. While similar to the FDA draft guidance, the EMA guidance differs slightly in its emphasis and lack of certain topics. For instance, there is no discussion of the role of the health care provider in the DCTs, but it emphasizes the importance of patient voice. The EMA guidance also features an extensive discussion on the need for investigator oversight.
The key remaining issues for DCTs include clarification around the roles and responsibilities of health care providers as well as principal investigator (PI) oversight and responsibility. All trials are different, but it’s important to ask the right questions and be clear in the protocol.
As IRBs and ethics committees review of DCTs, they can use newly developed recommendations for what should be submitted and discussions that should occur once the appropriate documents are submitted.
DCTs are not only more convenient for trial participants, but they often provide a positive return on investment for the trial itself. The DCT space is evolving and will require more commentary on guidance, sharing research, and effective implementation.
-As an early adopter of DCTs, could you share your experience and perspective on these issues? DCTs can make things easier for patients and the research more efficient. It can also contribute to providing more inclusive trials in solving some of the access issues that exist in healthcare and clinical trials. There are a lot of gray areas within the FDA guidance, but the key is to work together to address these challenges and ambiguities in order to ensure the safety and needs of the patients, while generating the knowledge necessary to further the trials.
-What is your response to questions surrounding the issue of adverse event reporting issue? A lot of questions on this topic have to do with the role of the health care provider as it relates to event reporting. The idea that health care providers in our communities may have data about an adverse event is not necessarily new, and health care providers are often aware of an adverse event very early on. Interstate licensing and our own institution’s policies are issues that still need to be addressed in terms of oversight and responsibilities. In some ways, health care providers are the same as any other data instrument in the trial – they are external data sources that come back to the investigator for safety and quality review.
The Grand Rounds session will be held on Friday, June 30, 2023, at 1:00 pm eastern.
Dr. Hernandez is a professor of medicine and director of the Duke Clinical Research Institute at Duke University; he is a co–principal investigator of the NIH Pragmatic Trials Collaboratory Coordinating Center. Dr. Tenaerts is the chief scientific officer of Medable, a cloud computing platform for decentralized clinical trials. Dr. Lipset is cochair of the Decentralized Trials & Research Alliance.
PROACT Xa was a prospective, randomized clinical trial conducted to determine whether apixaban was noninferior to warfarin in preventing valve thrombosis or valve-related thromboembolism in patients with an On-X mechanical aortic valve. The trial’s pragmatic design features enabled the investigators to conduct the the trial successfully during the COVID-19 public health emergency.
Dr. Alexander is a cardiologist and professor of medicine in the Duke University School of Medicine and a faculty member in the Duke Clinical Research Institute.
Dr. Garg is a professor of medicine, epidemiology, and biostatistics and the associate dean for clinical research in the Schulich School of Medicine & Dentistry. The MyTEMP trial is the first large, randomized trial to assess the effects of cooler dialysis fluid temperature on patient outcomes.
The QUARTET USA trial tested a novel approach to lowering blood pressure compared with standard-dose monotherapy. The trial was embedded within a network of federally qualified healthcare centers in the Chicago metropolitan area. Ciolino is an associate professor of preventive medicine (biostatistics) and director of the master of science in biostatistics program in the Northwestern University Feinberg School of Medicine.