Aug 18, 2023
By Geraldine Carroll, ASCO Publishing
The COVID-19 pandemic was a once-in-a-century crisis that changed the way we live and work. It is having a similarly transformative effect on how clinical trials are conducted.
The onset of the emergency posed a grave challenge to researchers as ongoing trials were disrupted by social distancing. But the complicated new circumstances initiated a flurry of innovation that is still evolving the process of research, diagnostics, and approving new therapies. New approaches promise to ease the burden of trials on patients, bring novel therapies into their communities, and improve diversity and enrollment in clinical trials.
“It’s important that we incorporate the lessons learned from the COVID-19 experience into our clinical trial designs and procedures, so our research is done faster, more effectively and equitably,” said Karen Reckamp, MD, clinical professor, director of the Division of Medical Oncology, and associate director for clinical research at the Cedars-Sinai Samuel Oschin Cancer Center. Dr. Reckamp is the lead investigator of the landmark, streamlined S2302 Pragmatica-Lung trial, the first-of-its-kind registrational-intent study that is poised to change the paradigm in clinical trials.1
Early in the pandemic, research regulators, sponsors, and funders introduced more flexibility in regulations and procedures. For example, the use of telehealth enabled reduced travel-related costs for patient visits that did not involve therapy.
To evaluate the changes in regulations, and potentially leverage some of the gains in the conduct of trials and care delivery during the pandemic, ASCO established a Steering Group on Cancer Care Delivery and Research in a Post-Pandemic Environment. The group included two multidisciplinary task forces focused on research and care delivery that culminated in recommendations in the ASCO Road to Recovery Report: Learning From the COVID-19 Experience to Improve Clinical Research and Cancer Care, published in December 2020.2
Among the report’s recommended goals is for interventional oncology trials to be streamlined to incorporate pragmatic and efficient design elements, such as the application of PRECIS-2 , to maximize learning from trial participants, increase generalizability of research results, integrate trial procedures more easily into standard clinical workflows, and reduce trial costs.
Today, the oncology community is focused on exciting novel approaches to modernize clinical trials.
“I think that the challenge that we all face now is how do we actualize that new view of clinical trials and the burden that it represents, and to continue to conduct a more patient-centric, equitable way of doing trials so that we don’t slip back into the pre-pandemic era—to take what we learned and move it forward,” said Michael Morris, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center and a special advisor to the director of the National Cancer Institute (NCI). Dr. Morris is also the co-director of the new NCI Clinical Trials Innovation Unit. The CTIU is a new collaborative interagency unit comprised of the FDA, NCI, and extramural investigators specifically designed to test innovative concepts using streamlined designs and accelerated review processes that will promote clinical trial equity and access.
Dr. Morris shared his perspective during a special session at the 2023 ASCO Annual Meeting, at which leaders from NCI and the U.S. Food and Drug Administration (FDA) leaders discussed innovative solutions to the challenges of cancer clinical trials.
The panelists emphasized that, ultimately, trial investigators should answer two key questions in designing a trial: “What are the essential questions that need to be answered from the trial?” and “What is the most effective way of conducting the trial?”
ASCO itself is active in the pragmatic trials space. The Society is the sponsor of the Targeted Agent and Profiling Utilization Registry Study (TAPUR), a pragmatic platform trial which has enrolled over 2,500 patients from more than 250 sites since 2016, and the trial continues to enroll new patients. TAPUR aims to collect data on clinical outcomes to learn about new uses of these drugs outside of FDA-approved indications, learn from the real-world practice of prescribing targeted therapies to patients whose tumors harbor a genomic variant known to be a drug target, educate oncologists about the implementation of precision medicine in clinical practice, catalog the choice of genomic profiling test by clinical oncologists, and learn about the utility of registry data to develop hypotheses for additional clinical trials.
Pragmatica-Lung Trial: A Model for Increasing Diversity and Enrollment
The Pragmatica-Lung trial—as well as the FDA’s Project Pragmatica, which the agency developed to explore such trials—seeks to reverse the trend of collecting a substantial amount of data, but instead focus on collecting only data that is required for regulator approval.
“It’s something that we at the FDA are very interested in…streamlining clinical trials, both in making the eligibility criteria of the trials themselves more representative of their drug’s use in the real world, and also reducing burdens on data collection, and asking, rather than collecting data for the sake of collecting data, what information do we really need to collect?” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence.
Pragmatica-Lung is a multidisciplinary collaboration involving the NCI, FDA, industry, academia, and advocacy groups that remarkably designed the trial in less than 6 months, effectively eliminating the delays that normally occur when multiple groups are involved in a trial. SWOG is leading the study in collaboration with the Alliance for Clinical Trials in Oncology and two other NCI National Clinical Trials Network (NCTN) groups, the ECOG-ACRIN Cancer Research Group and NRG Oncology.
Accelerating the Pace of Research Progress
The phase III Pragmatica-Lung trial will evaluate whether a combination of two FDA-approved agents, ramucirumab and pembrolizumab, improves overall survival compared to standard of care treatments in patients with advanced non-small cell lung cancer (NSCLC) whose disease has progressed after previous treatment with immunotherapy and chemotherapy.
The trial’s combination of ramucirumab and pembrolizumab was tested in an earlier randomized, phase II investigation that was part of the Lung-MAP study, S1800A, that evaluated the combination versus standard of care for patients who had previously received chemotherapy and immunotherapy with advanced NSCLC and had disease progression.3
“We’re really looking at one question [with Pragmatica-Lung], and that is the overall survival that we saw in S1800A,” said Dr. Reckamp. “And with that, we stripped away all the unnecessary data collection that comes along with other types of registrational issues in randomized phase III trials.” She said that investigators considered patient burden and how to pragmatically allow investigators to be empowered to treat patients as they normally would in their own practice.
“Moving forward, for types of trials where we have drugs whose toxicity profiles are well known as they are used in practice, and using novel combinations for a subset of patients who have limited treatment options available could really change the paradigm moving forward for these types of trials in multiple diseases,” Dr. Reckamp said.
Overcoming Disparities in Accrual
Pragmatica-Lung aims to enroll a representative group of 700 patients by implementing fewer eligibility criteria and other innovative approaches. The trial does not have exclusion criteria based on underlying comorbidities or require extensive laboratory testing prior to enrollment. There will be minimal data collection, and the trial will cover a broad spectrum of trial sites, including the more than 2,000 NCTN academic and community sites. There will be minimal changes to clinical delivery and resources, and the primary outcome of overall survival (OS) is simple and easy to measure.
All NCTN trials, including Lung-MAP and Pragmatica-Lung, have advocate involvement. “We have our DEI [diversity, equity, and inclusion] group and our community practices very well engaged to make sure that we have broad reach. Having this open through NCTN will ensure that we get this to multiple practices in far-reaching parts across the United States,” Dr. Reckamp said.
Narjust Florez, MD, a leading cancer health disparities expert, thoracic oncologist, and associate director of the Cancer Care Equity Program at the Dana-Farber Brigham Cancer Center, lauded Pragmatica-Lung’s first-of-its-kind multidisciplinary collaboration. She said taking the trial into the community is key and will likely increase the diversity of patients enrolled in the study.
“In oncology, we have been conducting drug development in the same way for decades despite new advances and the introduction of targeted therapy… We need to go where patients and vulnerable populations live.” Dr. Florez said. She praised the trial’s dedicated, plain-language website for enabling patients to understand the study: “That is equity—explaining the trial in words that people can understand.”
Dr. Pazdur said “the cry for greater diversity in clinical trials” was an important takeaway from the pandemic experience and has informed the FDA’s approach. “At the FDA, we have made [diversity] a really central issue of moving forward with clinical trials in drug regulation, looking at underserved populations here in the United States, and asking pharmaceutical sponsors to really address this issue with diversity plans in a prospective fashion,” he said.
Ensuring Representation in a Real-World Context
Intrinsic to the pragmatic design and concept of Pragmatica-Lung is that the population will be truly representative of the real world. Randomized controlled trials are considered the gold standard for evaluating efficacy of various interventions, and Harpreet Singh, MD, a division director at the FDA overseeing lung cancer drug development, said the strength of the study is that it retains the benefit of randomization while implementing pragmatic elements. These benefits include taking the trial to patients and incorporating practice into the trial, rather than the reverse, where patients enrolled on a traditional trial have visits that are outside of routine.
Dr. Singh added that a traditional randomized clinical trial typically has a more homogenous patient population because it has been designed around a de-risking strategy when a new drug goes to market.
“Part of the negotiation around designing this trial was the need for an increased sample size to try to account for some of what we expect to be perhaps unequal randomization, in terms of patient characteristics on either side, perhaps patients lost to follow-up, etc.,” she said. “When we talk about pragmatic trials, one element is that you probably often may need an increased sample size to account for the increase in heterogeneity, not only in your patient population but perhaps in monitoring as well.”
Jane Perlmutter, PhD, MBA, a patient advocate and long-term cancer survivor, said in any trial, accrual is just the first step. “It is important to recognize that accrual is only the first step; retention, which may require additional support during the trial for some participants, is also important,” she said. She recommended several approaches to ensure that the trial sample is representative of the to-be-treated population, such as reaching out to advocacy groups, being mindful of site selection, and keeping the trial open longer for inadequately represented groups.
As Pragmatica-Lung continues to enroll patients until the end of 2025, the study’s collaborators believe that it will serve as an excellent model for future studies to increase diversity and enrollment in clinical trials.
Making Pragmatic Trials a National Priority
Meanwhile, NCI’s Clinical Trails Innovation Unit (CTIU), which was launched in February, aims to advance innovative science, trial designs, and operational efficiencies for high-priority clinical research needs. The first proposal submission from researchers with NCTN was June 12. CTIU will accept trial proposals three times a year. The high-priority trials that are selected are to be suitable to innovative approaches with uncomplicated designs, using focused endpoints and data collection. CTIU trials will be conducted within NCTN and have a streamlined evaluation and activation process. CTIU anticipates that future proposals may include a broader group of collaborators beyond those at NCTN institutions.
Proposals may include:
- Clinical trials that investigate innovative therapeutic agents that have known safety data and show signs of efficacy
- Studies with novel designs, such as those with relaxed eligibility criteria, novel endpoints, pragmatic approaches, or other methods to deliver high-impact results to patients efficiently, effectively, and equitably
- New technologies or biomarkers that have been analytically validated and have good initial data supporting clinical utility
- Strategies that allow for more effective or equitable care
- New data collection methodologies or technologies that leverage existing electronic data systems
Researchers can address questions directly to the CITU at nciclinicaltrialsinnovationunit@mail.nih.gov
References
- NCT05633602. Ramucirumab Plus Pembrolizumab vs Usual Care for Treatment of Stage IV or Recurrent Non-Small Cell Lung Cancer Following Immunotherapy, Pragmatica-Lung Study. Available at: https://classic.clinicaltrials.gov/ct2/show/NCT05633602. Accessed July 13, 2023.
- Pennell NA, Dillmon M, Levit LA, et al. American Society of Clinical Oncology Road to Recovery Report: Learning From the COVID-19 Experience to Improve Clinical Research and Cancer Care. J Clin Oncol. 2021;39:155-69. Epub 2020 Dec 8. doi: 10.1200/JCO.20.02953.
- Reckamp KL, Redman MW, Dragnev KH, et al. Phase II Randomized Study of Ramucirumab and Pembrolizumab Versus Standard of Care in Advanced Non-Small-Cell Lung Cancer Previously Treated With Immunotherapy-Lung-MAP S1800A. J Clin Oncol. 2022;40:2295-306. Epub 2022 Jun 3. doi: 10.1200/JCO.22.00912.