For years, Sara worked in a hospital, making care possible for others. Now, after being diagnosed with breast cancer, she was the one in need of care.
Recently, TransCelerate gathered about 30 experts who are invested in advancing pragmatic clinical trials (PCTs): studies that bring research to patients in their usual health care settings. Represented groups included drug sponsors, CROs, academia, policymakers, physician researchers, data technology vendors, and industry consortia. I participated on behalf of both Parexel and the Association of Clinical Research Organizations (ACRO).
For two days, my colleagues and I talked through ideas for simplifying study processes, supporting clinicians, and fostering cooperation among all stakeholders. We’ll continue working to make PCTs more possible — and to make research more accessible for all patients.
While traditional trials investigate the benefits of a therapy when administered under ideal conditions, a PCT focuses on the impact of drugs in real-world situations. In a PCT, we are often researching ways to improve the effectiveness of a drug that has an established safety profile.
Pragmatic research gathers data through electronic health records (EHRs) and provider-patient interactions in clinics, hospitals, and other points of care. Compared to a classic randomized clinical trial (RCT), a PCT collects less data less invasively and uses broader inclusion criteria — both of which remove barriers to patient participation. As a result, PCT populations tend to be larger and more diverse than those in RCTs.
This greater diversity is important as we work toward equitable health care access for underrepresented groups. Additionally, researchers need to study drugs in diverse patient groups, which provide a fuller picture of how therapies impact real-world populations. In the New England Journal of Medicine, Ian Ford, Ph.D., and John Norrie, M.Sc., remind researchers of their responsibility to all subpopulations. “Medical researchers, both academic and commercial, must deliver health care innovations (drugs, devices, or other interventions) that are safe, beneficial, and cost-effective, and they must identify the subgroups for whom the innovation will provide the greatest benefit relative to risk,” they write. “A broad view of an intervention, including approaches to improve its effectiveness, is critical.”
The blinded RCT is recognized as the gold standard for clinical trials. Randomization allows for the control of unmeasured confounders — factors that may lead a person to receive one treatment over another that could cloud the ability to detect whether one treatment is better than another. While randomized trials are rigorous and provide high internal validity, these studies don’t focus on how a drug might work when used in routine clinical care rather than in optimal circumstances.
Increasingly, the FDA is supporting a spectrum of trial designs. These range from traditional, explanatory studies with strict eligibility criteria and numerous data measurements to studies that are truly conducted at the point of a patient’s clinical care using only real-world evidence drawn from a wide pool of patients, including those with comorbidities or age-related medical conditions — factors that could confound study data.
But the real-world nature of these studies should not negate their contributions to the body of evidence on the effectiveness and safety of medical interventions. “PCTs are not an abandonment of the scientific methods that have led to countless breakthroughs,” argues the National Institutes of Health’s Pragmatic Trials Collaboratory. “They don’t take away from basic science or diminish the importance of traditional RCTs.” RCTs and PCTs can complement each other. “No clinical trial is completely explanatory or pragmatic,” writes the Collaboratory.
In 2022, the FDA’s Oncology Center of Excellence established Project Pragmatica, which supports real-world research involving approved oncology therapies. As part of this project, the National Cancer Institute (NCI) has helped launched the Pragmatica-Lung Study. During our roundtable, we were privileged to hear from and discuss this study with Pragmatica-Lung study investigators.
The Pragmatica-Lung Study is a phase III trial that will evaluate whether two drugs approved to treat non-small cell lung cancer (NSCLC) can improve overall patient survival when used in combination. Researchers will enroll up to 700 adult patients from around the U.S. who have stage four or recurrent NSCLC and have previously received immune checkpoint inhibitors and chemotherapy. Enrolled patients will be treated with either the current standard of care or ramucirumab plus pembrolizumab, which have already received independent FDA approvals. Patients will participate through the cancer clinics in which they already receive care.
The Pragmatica-Lung Study uses broad inclusion criteria. Researchers will focus on overall survival. Overall survival is easily measured, which means the protocol won’t require imaging, labs, tissue collection, or patient-reported outcome instruments. By minimizing data collection, trial designers have reduced burdens both on patients and clinicians.
“These trials will make it easier for physicians who do not work in big academic medical centers to enroll their patients, resulting in participation by more diverse populations,” said the NCI’s James H. Doroshow, M.D., in a press release about the study. “Making trials more accessible, while upholding rigorous scientific and safety standards, means that more health care practitioners and patients will have an opportunity to participate.”
We believe the Pragmatica-Lung Study and similar studies can serve as models for future pragmatic trials. And while we are optimistic about the future of PCTs, roundtable participants also discussed the challenges we face. Perhaps most significantly, we must create research environments that attract a diverse group of patients. We will need expanded regulatory guidance on pragmatic designs. To facilitate data exchange, we’ll need greater compatibility among EHR platforms, which are at the core of clinic-based studies. We must also find ways to incentivize sponsors to launch PCTs as we support the clinicians who drive them.
None of these issues have simple solutions. But within the clinical research community, Parexel is collaborating to advance pragmatic approaches. It was a privilege to participate in TransCelerate’s roundtable and I look forward to opportunities to further engage in discussion, building on the success of the Pragmatica-Lung Study and similar clinical trials.
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