Cardiovasc Prev Pharmacother. 2020 Jul;2(3):85-98 Cardiovascular Prevention https://doi.org/10.36011/cpp.2020.2.e12 eISSN 2671-700X and Pharmacotherapy Special Article Pragmatic Clinical Trials for Real-World Evidence: Concept and Implementation Na-Young Jeong , BS, Seon-Ha Kim , BS, Eunsun Lim , BS, Nam-Kyong Choi , PhD Department of Health Convergence, Ewha Womans University, Seoul, Korea Received: Jun 30, 2020 ABSTRACT Accepted: Jul 28, 2020 Correspondence to The importance of real-world evidence (RWE) has been highlighted in recent years, and Nam-Kyong Choi, PhD the limitations of the classical randomized controlled trials, also known as explanatory Department of Health Convergence, Ewha clinical trials (ECTs), have been emphasized. Post-marketing observational studies have Womans University, 52 Ewhayeodae-gil, several problems, such as biases and incomparability between patient groups, and RWE Seodaemun-gu, Seoul 03760, Korea. E-mail: [email protected] can only be obtained after a certain period. Therefore, pragmatic clinical trials (PCTs) have garnered attention as an alternative to obtaining scientifically robust RWE in a relatively Copyright © 2020. Korean Society of short time. PCTs are clinical trials that have a pragmatic concept, i.e., the opposite of ECTs Cardiovascular Disease Prevention; Korean and are intended to help decision makers by evaluating the effectiveness of interventions in Society of Cardiovascular Pharmacotherapy. routine clinical practice. The characteristics of PCTs are the inclusion of various patients in This is an Open Access article distributed under the terms of the Creative Commons clinical practice, recruitment of patients in heterogeneous settings, and comparison with Attribution Non-Commercial License (https:// actual clinical treatments rather than a placebo. Thus, the results of PCTs are likely to be creativecommons.org/licenses/by-nc/4.0/) generalized and can have a direct impact on clinical and policy decision-making. This study which permits unrestricted non-commercial aimed to describe the characteristics and definitions of PCTs compared with those of ECTs use, distribution, and reproduction in any and to highlight the important considerations in the planning process of PCTs. To perform medium, provided the original work is properly cited. PCTs for the purpose of obtaining RWE, the contents covered in this study will be helpful. ORCID iDs Keywords: Causality; Epidemiologic studies; Patient outcome assessment; Na-Young Jeong Pragmatic clinical trials https://orcid.org/0000-0003-2130-1286 Seon-Ha Kim https://orcid.org/0000-0003-0661-8365 Eunsun Lim INTRODUCTION https://orcid.org/0000-0002-3242-5682 Nam-Kyong Choi Traditionally, randomized controlled trials (RCTs) in controlled settings have been https://orcid.org/0000-0003-1153-9928 considered the gold standard for studying the efficacy of health interventions.1) It is the Conflict of Interest backbone of clinical research because randomization in well-defined and controlled settings The authors have no financial conflicts of can improve the internal validity and reduce bias, but these settings tend to overestimate the interest. benefits and underestimate the risks.2) Recently, there has been great interest in conducting Author Contributions post-launch observational studies that increase the external validity using real-world data Conceptualization: Jeong NY, Choi NK; (e.g., claims data and electronic health records [EHRs]) including a large population.1)3) Investigation: Jeong NY, Kim SH, Lim E, Choi However, several challenges have been reported when conducting these studies, including NK; Supervision: Choi NK; Writing - original bias (e.g., selection bias), inaccuracy of diagnostic codes, and incomparability between draft: Jeong NY, Kim SH, Lim E; Writing - patient groups.4)5) In terms of real-world evidence (RWE) delivery, pragmatic clinical trials review & editing: Jeong NY, Kim SH, Lim E, Choi NK. (PCTs) are proposed as a method to provide evidence in a relatively shorter time to solve https://e-jcpp.org 85 Cardiovascular Prevention Pragmatic Clinical Trials for Real-World Evidence and Pharmacotherapy problems faced by multiple stakeholders in the real world.6) PCTs combine the scientific rigor of RCTs with the real-life application of observational studies to suggest better solutions that reflect daily clinical practices.6) PCTs randomize patients and evaluate the effectiveness rather than efficacy of the intervention (treatment) to investigate the validity of the intervention in a broad routine clinical setting.7) PCTs are also referred to as pragmatic randomized clinical trials or embedded pragmatic clinical trials (ePCTs). With the recent increase in the importance and availability of RWE, interest in PCTs has increased worldwide. When searching using PubMed, more than 600 of the included trials conducted between 1977 and 2017 were “pragmatic” in their titles, while more than half of them were concentrated from 2014 to 2017.8) In Korea, the National Evidence-based healthcare Collaborating Agency organized a research center to support and fund trials including PCTs in 2019, which has identified the effectiveness of health care technologies and provided evidence for regulatory decisions. Given these circumstances, it is necessary to understand the concept and implementation of PCTs. In this study, we briefly described the main ideas and planning stages of PCTs and the key considerations required to perform them. CONCEPT OF PCTs The concept of pragmatism in trials was first presented by Schwartz and Lellouch in 1967. 9) They classified randomized trials into 2 categories, “explanatory” and “pragmatic,” depending on the conditions of comparison and the level of current practice. Explanatory clinical trials (ECTs) are intended to provide information to understand the efficacy and biological mechanisms of interventions by comparing them in the identical and strict conditions under controlled settings.9) By contrast, PCTs aim to assess the effectiveness of interventions in the usual clinical setting and to make relevant decisions.7)9) After the initial concept of PCTs was presented, a variety of factors have been presented by several authors to distinguish ECTs from PCTs (Table 1).10-16) ECTs determine whether the intervention actually work in controlled environments, while PCTs assess whether the intervention work in real-world settings.14) Other differences between the 2 representative trials are as follows: Participants: ECTs use high levels of inclusion and exclusion criteria to select the appropriate research targets. However, PCTs minimize the exclusion criteria to include a variety of patients visiting the routine clinical sites. Table 1. Comparison of the attributes that distinguish ECTs and PCTs Feature ECTs PCTs Question Efficacy: does the intervention work under ideal setting? Effectiveness: does the intervention benefit when used in routine practice? Inclusion criteria of participants Strict criteria to exclude high-risk or poorly adherent participants Broader criteria to include various participants Setting Highly controlled experimental setting Normal practice setting Intervention Thorough delivery and monitoring of intervention Flexible delivery and monitoring of intervention Comparator Generally placebo control Routine clinical treatment, mostly not placebo control Outcomes A restricted set of events or surrogated outcomes A broad set of events or determined in the routine course of clinical practice Sample size Comparatively small Comparatively large Relevance to practice Low relevance to practice High relevance to practice Follow-up period Relatively short-term follow-up Relatively long-term follow-up ECT = explanatory clinical trial; PCT = pragmatic clinical trial. https://e-jcpp.org https://doi.org/10.36011/cpp.2020.2.e12 86 Cardiovascular Prevention Pragmatic Clinical Trials for Real-World Evidence and Pharmacotherapy Settings: ECTs are performed in strictly controlled settings to minimize bias. By contrast, PCTs are performed in multiple institutions that cover the full range of actual clinical trials, not in a single center, to maximize applicability and generalizability. Intervention: ECTs provide specific directions, so that the delivery of intervention and compliance with intervention are closely monitored. However, PCTs leave the providers with details of the implementation of intervention as in the normal practice and do not require compliance with the interventions. Comparator: ECTs recommend that the therapeutic impact of experimental interventions be compared with placebo, but PCTs generally compare the relative effectiveness of the treatment studied with the treatment currently used in practice instead of the comparing it with a placebo. Outcomes: PCTs focus on a broad set of patient-centered outcomes or endpoints; however, ECTs have limited or surrogate measurable outcomes, especially clinical symptoms or biological markers. Consequently, PCTs have high relevance to real life and direct social value than ECTs because they are more likely to be applied to practice at once.17) Based on these factors, Califf and Sugarman11) defined PCTs as “designed for the primary purpose of informing decision makers regarding the comparative balance of benefits, burdens, and risks of a biomedical or behavioral health intervention at the individual or population level”. Explanatory and pragmatic trials should not be considered as completely dichotomous, but should be seen as two extremes within the concept of