Pragmatic randomized controlled trials: strengthening the concept through a robust international collaborative network: PRIME-9-Pragmatic Research and Innovation through Multinational Experimentation

Abstract

In an era focused on value-based healthcare, the quality of healthcare and resource allocation should be underpinned by empirical evidence. Pragmatic clinical trials (pRCTs) are essential in this endeavor, providing randomized controlled trial (RCT) insights that encapsulate real-world effects of interventions. The rising popularity of pRCTs can be attributed to their ability to mirror real-world practices, accommodate larger sample sizes, and provide cost advantages over traditional RCTs. By harmonizing efficacy with effectiveness, pRCTs assist decision-makers in prioritizing interventions that have a substantial public health impact and align with the tenets of value-based health care. An international network for pRCT provides several advantages, including larger and diverse patient populations, access to a broader range of healthcare settings, sharing knowledge and expertise, and overcoming ethical and regulatory barriers. The hypothesis and study design of pRCT answers the decision-maker's questions. pRCT compares clinically relevant alternative interventions, recruits participants from diverse practice settings, and collects data on various health outcomes. They are scarce because the medical products industry typically does not fund pRCT. Prioritizing these studies by expanding the infrastructure to conduct clinical research within the healthcare delivery system and increasing public and private funding for these studies will be necessary to facilitate pRCTs. These changes require more clinical and health policy decision-makers in clinical research priority setting, infrastructure development, and funding. This paper presents a comprehensive overview of pRCTs, emphasizing their importance in evidence-based medicine and the advantages of an international collaborative network for their execution. It details the development of PRIME-9, an international initiative across nine countries to advance pRCTs, and explores various statistical approaches for these trials. The paper underscores the need to overcome current challenges, such as funding limitations and infrastructural constraints, to leverage the full potential of pRCTs in optimizing healthcare quality and resource utilization.

Fig. 1

Efficacy versus effectiveness. The illustration depicts the contrast between a classical randomized controlled trial (RCT), which is rigorously controlled and focused on internal validity (efficacy), and a pragmatic RCT, which is intended to mirror clinical practice in the real world and optimized for external validity (effectiveness). When assessing the effectiveness and safety of interventions, healthcare decision-makers must consider both types of trials. Classical RCTs furnish valuable insights into an intervention’s efficacy in a highly controlled environment, while pragmatic RCTs yield insights into an intervention’s real-world performance, potentially offering more comprehensive generalizability. If an intervention proves ineffective in terms of its effectiveness, decision-makers may need to consider prioritizing healthcare resources based on the ethical principle of justice

Fig. 2

Comparison of Bayesian and frequentist statistics. A Bayesian analysis workflow—this panel illustrates the essential components of Bayesian analysis, including the incorporation of prior probabilities, the calculation of likelihood based on observed data, and the computation of posterior probabilities using Bayes’ theorem. The iterative nature of Bayesian updating is also depicted, highlighting the adaptability of the approach as new evidence becomes available. B Frequentist analysis workflow—in contrast, this panel demonstrates the frequentist analysis workflow, which involves estimating parameters based solely on the likelihood of observed data. The focus is on hypothesis testing and the calculation of p-values, without the incorporation of prior knowledge

Fig. 3

Organization and advantages of the platform pragmatic clinical trials. The potential next step in developing the PRIME-9 collaboration will be the organization and advantages of platform pragmatic clinical trials (ppRCT). Platform trials can test multiple interventions simultaneously within a single trial, allowing for the streamlined development of effective therapies and the ability to adapt to changing scientific knowledge. These trials would follow the principles of pragmatic trials, focusing on patient-centered outcomes, efficiency, and flexibility. By conducting ppRCT, the PRIME-9 collaboration can evaluate the effectiveness of multiple interventions for a particular health condition or disease cost-effectively and adaptively. The addition of ppRCT would represent a significant advancement for the PRIME-9 collaboration in their mission to improve patient outcomes and advance healthcare practice worldwide

Fig. 4

The PRIME-9 collaboration. The PRIME-9 collaboration is an international network of healthcare professionals and researchers who are collaborating to conduct pragmatic clinical trials. This collaboration includes nine countries, namely Sweden, Canada, Denmark, the UK, the USA, Netherlands, Germany, Australia, and New Zealand. The objective of the PRIME-9 collaboration is to investigate vital clinical questions by conducting extensive, real-world studies that represent the diversity of patients and healthcare settings. Pragmatic clinical trials concentrate on the effectiveness of interventions in real-world settings rather than the efficacy of interventions in controlled environments. By conducting these trials, the PRIME-9 collaboration seeks to provide valuable insights into the best practices for treating and managing various health conditions. The partnership includes a multidisciplinary team of researchers, clinicians, and patient advocates working together to design and execute relevant and meaningful studies for patients and healthcare providers. Country-level pragmatic RCTs will be pooled into a master-level RCT, allowing the PRIME-9 collaboration to conduct studies on a larger scale and more efficiently than individual research teams