The Good Clinical Trials Collaborative has opened a 6-week public consultation period on its draft guidance for randomized controlled trials. The consultation period will last until September 15.
Launched in June 2020 with the support of Wellcome, the Bill & Melinda Gates Foundation, and the African Academy of Sciences, the Collaborative is developing guidance “to enable and promote informative, ethical, and efficient randomized controlled clinical trials.” The purpose of the guidance is to identify the fundamental principles of randomized controlled trials and enable their application to a wide range of healthcare settings and interventions.
Edward Mills, PhD, FRCP Professor Department of Health Research Methods, Evidence & Impact McMaster University, Canada
Topic
Early Treatment of COVID-19 with Repurposed Therapies: The TOGETHER Adaptive Platform Trial
Keywords
COVID-19 treatment; Adaptive Platform Trial; Fluvoxamine; Repurposed therapies, TOGETHER Trial
Key Points
The most successful clinical trials have 1 thing in common; they are all Adaptive Platform Trials with an overarching master protocol that plans for changes in the long term, such as changing the intervention.
Perpetual trials are key to effective adaptable trials, where the focus is to build a trial infrastructure that is not abandoned at the end of the trial, but repurposed to quickly and efficiently begin another trial.
The TOGETHER Trial is a randomized Adaptive Platform Trial studying repurposed therapies to treat COVID-19.
In the TOGETHER Trial, participants were randomized to either a placebo arm of the study, or to a repurposed therapy arm of the study. If a particular repurposed therapy didn’t show significant benefit for COVID-19 patients, that arm of the study was discontinued and an additional repurposed therapy was introduced in a new arm of the study.
After many trial therapies showed little effect, Fluvoxamine, an SSRI commonly used for depression, has shown promising results when repurposed to treat COVID-19.
Discussion Themes
With important breakthroughs on COVID treatments, should we wait until a study is completed, accepted by a journal, and published before disseminating the findings?
Final results on the of Fluvoxamine trials are not yet available, but given the data thus far, there are no major concerns about the safety and tolerability of this medication.
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:
In the latest episode of the NIH Collaboratory Grand Rounds podcast, Dr. Adrian Hernandez and Dr. Susan Ellenberg continue their discussion about the challenges of DSMBs and COVID-19 trials. The full March 5 Grand Rounds webinar with Dr. Ellenberg is also available.
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
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.
Renato D. Lopes, MD, MHS, PhD Professor of Medicine Division of Cardiology Duke University Medical Center Duke Clinical Research Institute Brazilian Clinical Research Institute
Topic
Generating High-Quality Evidence During a Pandemic: The Brazilian COALITION Experience
The SARS-CoV-2 infection affects the cardiovascular system and is associated with complications such as myocardial ischemia, myocarditis, arrhythmias, and thromboembolic events. These manifestations result mainly from the intense systemic inflammatory response and disorders of the coagulation system.
The COALITION collaborative includes several major Brazilian hospitals and research networks with the aim of accelerating multicenter randomized controlled trials that generate high-quality evidence to guide the treatment of patients with COVID-19.
To move toward a world in which most clinical decisions are supported by high-quality evidence requires structural changes in the clinical trials ecosystem.
Discussion Themes
How did you overcome contractual and regulatory concerns to execute your trials?
Instead of “publish or perish,” it should be “collaborate or perish.” Collaboration is the key to surviving in modern academic medicine.
Trevor Lentz, PT, PhD, MHA Assistant Professor in Orthopaedic Surgery Duke Clinical Research Institute
Lesley Curtis, PhD Chair and Professor, Department of Population Health Sciences Duke University School of Medicine
Frank Rockhold, PhD, ScM, FASA, FSCT Professor of Biostatistics and Bioinformatics Duke Clinical Research Institute
Topic
Designing, Conducting, Monitoring, and Analyzing Data from Pragmatic Clinical Trials: Proceedings from a Multi-Stakeholder Think Tank Meeting
Keywords
Pragmatic clinical trials; Think tank; Risk-based monitoring; Data quality; Real-world data; Electronic health records
Key Points
Pragmatism in study design is not a binary concept: some trial elements are purely explanatory (to establish efficacy in ideal settings) and some elements are purely practical (to establish effectiveness in the real world). The study design must serve the research question.
Findings from the think tank discussions on best practices and actionable steps included:
Ask precise research questions, and select the appropriate degree of pragmatism.
Optimize data quality through study design.
Focus on primary endpoints in data capture to maximize likelihood of success.
Innovate on mechanisms for data capture.
Promote adherence to the study protocol.
Evolve trial operations staff to focus on data science and informatics.
Share learning experiences openly and widely.
Discussion Themes
There is a misconception that PCTs, because they pursue pragmatism, are less rigorous and conducted without proper oversight or adherence to a protocol. Quality by design and good clinical practice principles apply equally to PCTs.
Risk-based monitoring is a potentially dynamic system that could improve study safety and quality, and make better use of study resources.
There is great interest from regulators, sponsors, and the academic research community to move PCT methods forward. To achieve this, we need to see more examples of successful PCTs in a context of regulatory decision-making.
Read the proceedings from the think tank meeting published in Therapeutic Innovation & Regulatory Science.
A recent Grand Rounds webinar presented by C. Michael Gibson, MS, MD, described how open access, patient empowerment, social media, and digital health are transforming clinical trials. Dr. Gibson is a professor of medicine at Harvard Medical School and president and CEO of Baim and PERFUSE Research Institutes.
Among the key points:
The COVID-19 pandemic has been a call to arms to physicians to combat not only the virus but the misinformation.
As the internet is replacing the printing press, “copyleft” is replacing copyright in this new open-access era. It is a participatory community with bidirectional flow of information through social media.
Health data does not equal health care. Patients are looking to physicians to curate health information.
In this new world of clinical research, patients are enrolling in virtual trials via a phone app and will be followed up online through claims data and patient-reported outcomes.
Patient-empowered trials have the potential to provide more generalizable study results and to lead to patient-specific predictions through use of artificial intelligence.
C. Michael Gibson, MS, MD Professor of Medicine Harvard Medical School President and CEO Baim and PERFUSE Research Institutes
Topic
The Democratization of Medicine: Open Access, Social Media, AI, Apps, and Empowering the Patient as the Future of Clinical Research
Keywords
Clinical research; Open access; Social media; Artificial intelligence; Heartline study; WikiDoc; WikiPatient
Key Points
As the internet is replacing the printing press, “copyleft” is replacing copyright in the open-access era. It is a participatory community with bidirectional flow of information through social media.
Health data does not equal health care. Patients are looking to physicians to curate health information from huge volumes of data.
Social media and open access during the COVID-19 pandemic has meant that physicians are citizen journalists, innovators, activists, and educators.
In this new world, patients are enrolling in virtual trials via a phone app and will be followed up online through claims data and patient-reported outcomes.
Discussion Themes
The COVID-19 pandemic has been a call to arms to clinicians to combat not only the virus but the misinformation. As educators we must set the path and not allow uninformed people to take control.
Enabling patient-empowered trials has the potential for more generalizable study results and can lead to patient-specific predictions through use of artificial intelligence.
How do we validate the quality of open-access data and reports that are not peer-reviewed?
How can we diminish the hazards of skewed research outcomes arising from trial participant conversations on social media?
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.
The Good Clinical Trials Collaborative has opened a 6-week public consultation period on its draft guidance for randomized controlled trials. The consultation period will last until September 15.
In the latest episode of the