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Embedded Pragmatic Clinical Trials

Background

The growing infrastructure of the learning health systems has created an opportunity for increasing the number of randomized studies evaluating the value and harms of health interventions in real world use through Embedded Pragmatic Clinical Trials (EPCTs).1 In contrast to traditional explanatory randomized controlled trials which are performed under highly controlled conditions and whose processes are largely conducted outside of the clinical care environment, the majority of EPCTs procedures are integrated into routine clinical care processes leveraging existing health system resources including clinical personnel, workflows and data capture through the EHR.2,3. While not appropriate for every intervention, EPCTS offers unique advantages and challenges to relative to traditional explanatory trial designs.4

Advantages of the EPCTS over traditional explanatory randomized controlled trials5:

Speed and Efficiency:

Because EPCTs are integrated directly into real-world clinical settings it allows researchers to use existing health care infrastructure and data systems to conduct the trial, reducing the need for additional resources and time typically required to set up a traditional RCT. For instance, EPCTs utilize routinely collected health data from the EHRs to measure process and health outcomes. This approach minimizes the need for additional data collection and data entry efforts, accelerating the overall trial process. In contrast traditional RCTs involve extensive primary data collection, including patient recruitment, consent, and follow-up, which can significantly prolong the duration of the trial and add significant expense.

Real-World Effectiveness: Pragmatic trials assess the effectiveness of interventions in real-world clinical settings thereby enhancing the external validity of their results EPCTs provide insights into how interventions work in the typical clinical settings where they will be used. This in contrast with traditional explanatory RCTs which often use highly selected populations and rigid study protocols and controlled environments which enhance their internal validity but reduce their external validity. Because the results of EPCTs are more directly applicable to real world practice they are more informative to policy makers as they provide evidence that is immediately relevant and easily interpretable by health system decision-makers.

Limitations of EPCTs

While EPCTs offer numerous advantages, they also have limitations compared to traditional explanatory RCTs which include5:

Control and Internal Validity: EPCTs often have less control over the implementation of the intervention and the environment in which it is tested. This lack of control can introduce more variables that may confound the results, potentially reducing the internal validity of the trial compared to traditional RCTs, which are highly controlled and standardized.

Selection Bias and generalizability: Since EPCTs are conducted in real-world settings and often use existing healthcare infrastructures for participant recruitment, there may be inherent biases in who participates. Patients who seek treatment at certain sites or agree to participate in such trials might not be representative of the general population, leading to selection bias.

Although EPCTs are praised for their enhanced external validity relative to explanatory trials, their results might only be generalizable to similar healthcare settings and may not apply universally given the diversity of health system contexts.

Data quality and completeness: EPCTs rely on routine clinical data, which can vary in quality and completeness. Inconsistent data collection and entry practices across sites can lead to challenges in data interpretation and limit the robustness of the trial findings.

Ethical and Regulatory Challenges6–8: The integration of research into clinical care can also raise ethical and regulatory challenges. For instance, when can does a study require written consent of the patient vs a postcard consent? Ensuring patient privacy, informed consent, and adherence to regulations can be more complex in the flexible and integrated framework of an EPCT.

Infrastructure Required for EPCTs

For EPCTs to be effectively performed, the following infrastructure is essential:

Data Systems: Robust EHRs and comprehensive data warehousing are critical. These systems need to be interoperable to facilitate seamless data exchange and integration.

Governance and Ethics: It is crucial to establish clear governance structures and ethical frameworks to navigate the conduct of EPCTs, ensuring both patient safety and data privacy.

Stakeholder Engagement: The involvement of all stakeholders, including patients, healthcare providers, health system leaders and policymakers is crucial. This engagement ensures that the trials are relevant and that the findings are can be quickly implemented into practice.

Multidisciplinary Collaboration: A multidisciplinary team is essential, including clinicians, statisticians, data scientists, and IT professionals, for the design, execution, and analysis of EPCTs.

Challenges to Performing Embedded Pragmatic Trials

Several challenges impact the implementation of EPCTs within LHSs5:

Alignment with Operational Priorities and Costs: Delivery systems often require that research studies align with their operational priorities, existing IT capabilities, and standard quality improvement procedures, which can limit the scope and design of PCTs.Concerns about direct and indirect costs, and the potential unrecoverable costs of conducting the research within healthcare settings.

Research Governance and Regulatory Challenges: The process of research governance was often cited as a barrier due to the time it adds and the inconsistency in determinations about risk levels and consent requirements. Specific challenges include the lengthy time required for approval processes and the difficulty in fitting the methodological rigor and end points required by external funders into routine clinical practice.

Data Integration and Collection: The reliance on existing data collection systems (like electronic health records) can pose limitations if these systems are not compatible with the research needs or if additional data collection disrupts clinical operations.

Clinical Integration and Stakeholder Buy-In: Integrating the trial interventions within the standard clinical workflows without causing significant disruptions is a major challenge. This includes the burden placed on clinicians to recruit patients, obtain informed consent, and manage additional data recording. Changes in leadership or strategic priorities within healthcare systems during a study can lead to shifts in support for ongoing research.

The complexities and opportunities inherent in EPCTs suggest that addressing these challenges requires not only technical solutions but also adaptive changes in healthcare culture and practices.

References

1. Tuzzio L, Larson EB. The Promise of Pragmatic Clinical Trials Embedded in Learning Health Systems. EGEMS (Wash DC). 2019;7(1):10.

2. Thorpe KE, Zwarenstein M, Oxman AD, et al. A pragmatic-explanatory continuum indicator summary (PRECIS): a tool to help trial designers. CMAJ. 2009;180(10):E47-57.

3. Ford I, Norrie J. Pragmatic Trials. N Engl J Med. 2016;375(5):454-463.

4. Zuidgeest MGP, Goetz I, Groenwold RHH, et al. Series: Pragmatic trials and real world evidence: Paper 1. Introduction. J Clin Epidemiol. 2017;88:7-13.

5. Cocoros NM, Gurwitz JH, Cziraky MJ, et al. Pragmatic guidance for embedding pragmatic clinical trials in health plans: Large simple trials aren’t so simple. Clin Trials. 2023;20(4):416-424.

6. Kim SYH. Ethical issues in pragmatic trials of “standard-of-care” interventions in learning health care systems. Learn Health Syst. 2018;2(1):e10045.

7. Faden RR, Kass NE, Goodman SN, Pronovost P, Tunis S, Beauchamp TL. An ethics framework for a learning health care system: a departure from traditional research ethics and clinical ethics. Hastings Cent Rep. 2013;Spec No:S16-27.

8. Califf RM, Sugarman J. Exploring the ethical and regulatory issues in pragmatic clinical trials. Clin Trials. 2015;12(5):436-441.

Submitted by (Anna Maw)