Bridging research and practice: enhancing regulatory decisions with pragmatic clinical trials in oncology

Introduction

Pragmatic clinical trials (PCTs) evaluate the effectiveness of interventions in settings that more closely resemble real-world settings, aiming to produce evidence directly applicable to clinical practice. There is growing interest in using PCTs as alternatives to explanatory clinical trials to support regulatory decision making. Explanatory clinical trials represent the conventional approach, driven by familiarity with the methodologies and acceptance by regulatory authorities.¹ Advocating for a shift away from the conventional trials toward PCTs highlights the need for evolving clinical trial designs to enhance research impact. This shift reflects growing recognition of the challenges with conventional trials, such as increasing design complexity and highly selected patient populations.

To aid in adopting PCTs, drug sponsors may consider a hybrid approach, integrating pragmatic elements into traditional randomized controlled trials to streamline research, enhance data relevance, ease patient burden, and expand access to diverse patient populations. A ‘hybrid PCT’ balances real-world applicability with rigorous scientific methodologies, addressing challenges with conventional trial approaches while leveraging the benefits of pragmatic approaches. In oncology drug development, incorporating pragmatic elements can accelerate the availability of new therapies and ensure the adaptability of research findings to clinical practice while meeting regulatory standards.

Design principles of clinical trials with pragmatic elements

Hybrid PCTs blend conventional methodologies with pragmatic elements to meet specific research goals.² This integration aims to reflect real-world conditions and align with regulatory frameworks. Explanatory trials often operate under controlled conditions with stringent eligibility criteria, appropriate for new molecular entities with limited safety data early in development. Such trials require rigorous tumor measurement and patient follow-up to ensure a comprehensive assessment of response and safety. These trials often enroll homogenous populations to minimize confounding factors and isolate drug effects. This control can simplify measuring treatment effects but can result in complex protocols, limiting eligible sites and patients.

In comparison, trials with pragmatic elements can enhance the trial result applicability across broader patient populations by reflecting everyday healthcare settings. This is achieved through hallmarks such as broadened eligibility criteria, accommodating patients with comorbidities, poorer performance status, and older patient populations (Figure 1).2, 3, 4, 5 Other pragmatic features are flexible treatment delivery, and streamlined data collection, relevant for therapies with known mechanisms of action or those not first-in-class. The suitability of therapies for trials with pragmatic elements depends on having an established safety profile, a wider therapeutic index, and the feasibility of administration in nonacademic settings.

Figure 1.

Hallmarks of pragmatic clinical trials for application in hybrid designs. These features are indicative of a pragmatic approach, although not all need to be present for a trial to be classified as pragmatic. The inclusion of these elements can vary, reflecting a spectrum rather than an all-or-nothing requirement.

Clinical trials with pragmatic elements can leverage components to enhance the relevance and applicability of their findings, such as using real-world data (RWD) and real-world evidence from electronic health records, registries, and patient-reported outcomes. These sources ensure the trial setting mirrors real-world environments. Many PCTs focus on comparative effectiveness, providing direct evidence of the relative benefits and risks between treatment options. These trials prioritize outcomes such as overall survival (OS), patient experience, and quality of life, aligning with patient and clinician priorities. Tumor-based endpoints, such as progression-free survival, may not routinely be included in a fully pragmatic study; however, they may still be deployed in hybrid PCTs with other trial elements more pragmatic, such as selective safety data collection or broadened eligibility criteria. In addition, more pragmatic intermediate disease endpoints such as time-to-discontinuation and time-to-next-treatment can be considered indicators of greater treatment effectiveness.⁶

Pragmatica-Lung: A case study in pragmatic clinical trial design

Pragmatica-Lung (NCT05633602) is a case study for integrating pragmatic elements into an oncology trial.⁷ The trial evaluates a novel combination regimen within a real-world context, aiming for regulatory submission based on clinically meaningful outcomes.^8,9 The design reflects a fully pragmatic approach: broadened eligibility criteria to encompass diverse patient profiles and streamlined data collection prioritizing critical safety and efficacy endpoints. This helps mitigate participant and site burden, enhances enrollment rates, ensures the relevancy of findings to a broader population, and expedites the drug development timeline. By reducing administrative and financial burdens, Pragmatica-Lung can make the trial more cost-effective and attractive to sites, accelerate the time to activate a trial, and be less disruptive to patients.

In Pragmatica-Lung, the endpoints align with the primary research question: does ramucirumab plus pembrolizumab extend OS compared with standard of care? Both therapies in this novel combination are Food and Drug Administration (FDA) approved and have extensive safety and efficacy data as monotherapies for non-small-cell lung cancer. Rather than measuring tumor size reduction or disease progression, the trial measures OS as the primary outcome and incidence of severe adverse events as the secondary outcome. This minimizes radiographic scans and additional visits, prioritizing survival measures and key safety signals. This regulatory-focused approach implements an efficacy endpoint that is simple to measure and acceptable to regulators. Pragmatica-Lung was rapidly implemented within 7 months and is available at >500 sites across the National Clinical Trials Network. It is on pace to complete enrollment in half the estimated timeframe across a more representative set of patients compared with historical rates, demonstrating the efficiency and ability of PCTs to reach more patients.¹⁰

Other examples of PCTs are the Targeted Agent and Profiling Utilization Registry (TAPUR) study, exploring the effectiveness and safety of approved cancer therapies used for genomic indications not in the FDA-approved label.¹¹ Although the number of PCTs in oncology is difficult to quantify, their use for regulatory decision making remains limited.¹²

Regulatory considerations for clinical trials with pragmatic elements

Pragmatica-Lung extensively incorporated pragmatic elements due to both products being approved for the same population and supported by substantial efficacy and safety data. Not all trials need to be as pragmatic; integration of pragmatic elements can be tailored based on known drug characteristics and research questions. The use of pragmatic elements does not necessarily need to be limited to situations where a product is late in its development lifecycle. Early regulatory engagement is critical to align on pragmatic elements’ acceptability and required for drug assessment and approval. These interactions ensure trial designs adhere to regulatory expectations while leveraging flexibilities associated with pragmatic trial elements. Given differing familiarity and acceptance among health authorities, it is essential to align with health authorities where submission has been prioritized. Programs such as FDA’s Project Pragmatica and Project 5 in 5 exemplify the growing endorsement of PCTs to support regulatory decision making while reducing complexity and improving the generalizability of data.^13,14 In addition, the FDA’s C3TI program has initiatives focused on Bayesian supplementary analysis, selective safety data collection, and streamlined trials embedded in clinical practice, highlighting further commitment to enhancing trial efficiency and relevance through innovative trial designs.¹⁵

Challenges and future directions

Conducting oncology research is challenging due to high costs and logistical complexities. Simplified study protocols and data collection processes can lessen the burden on participants and providers, improving recruitment, retention, and compliance. Aligning trials with clinical workflows minimizes disruptions and ensures settings mirror real-world environments. This can also enable additional sites to implement the study, enabling access to more patients.^16,17

While offering advantages, trials with pragmatic elements can present challenges that must be navigated carefully, especially when intended for regulatory use. Early engagement with regulatory authorities is necessary to align on the acceptability of pragmatic elements and data adequacy for benefit–risk assessments. Operational complexities may arise when integrating research into routine care, requiring investments in infrastructure and training. Balancing pragmatism with scientific rigor remains critical. The degree of pragmatism will depend heavily on the phase of the trial and the safety profile of the treatment under study.

Variability in data quality and consistency can vary in less controlled settings depending on the types of pragmatic elements incorporated into a study design, which can complicate interpretation. For example, broad inclusion criteria, while beneficial for generalizability, can introduce variability. Use of electronic health records, digital health technologies, and other RWD sources should be evaluated to ensure they are suitable for answering the research question. Integrating RWD into trials allows researchers to observe the interaction of new therapies with standard treatments and understand the practicalities of their use in typical healthcare environments. It also aids in identifying patient subgroups that benefit most from certain treatments, a crucial aspect of personalized medicine in oncology. However, RWD quality, completeness, and consistency are concerns given that it is collected for various purposes beyond research. Lack of data interoperability between different healthcare systems and the absence of standardized collection methods also complicate aggregation and analysis of RWD. Trials with pragmatic elements should have robust methods for data verification and validation to meet regulatory standards.

To successfully incorporate pragmatic elements into future trials, several key strategies are necessary. First, there is a need to continue broadening patient inclusion criteria to ensure that trial populations accurately reflect the diversity seen in clinical practice. Second, a greater emphasis should be placed on patient-relevant outcomes. Third, leveraging technological advancements and data science to harness RWD effectively will be important. Fourth, prospective agreement among stakeholders on core data elements, processes for collection, and analyses to be carried out will help ensure successful implementation and maximize the utility of the results.

Conclusion

Integrating pragmatic elements into oncology trials to create hybrid PCTs offers a promising avenue for efficient, relevant, and patient-centered drug development. Collaboration with patient advocacy groups, providers, regulators, pharmaceutical companies, and other stakeholders ensures trial designs are patient-centric and reflective of real-world practice. Sharing experiences, challenges, and successes in designing and implementing clinical trials with pragmatic elements will build a knowledge base to guide future trials.

By addressing challenges and capitalizing on opportunities, the drug development community can make significant strides in advancing cancer care. The future of oncology trials is poised to embrace pragmatic elements, aiming to bridge the gap between research and practice, ultimately improving patient care and outcomes.