Pragmatic Free Trial Meta
Pragmatic Free Trial Meta is a non-commercial open data platform and infrastructure that facilitates research on pragmatic trials. It is a platform that collects and shares clean trial data and ratings using PRECIS-2 allowing for multiple and diverse meta-epidemiological studies to evaluate the effect of treatment on trials that have different levels of pragmatism, as well as other design features.
Background
Pragmatic studies provide real-world evidence that can be used to make clinical decisions. However, the use of the term "pragmatic" is inconsistent and its definition and assessment requires further clarification. The purpose of pragmatic trials is to inform clinical practice and policy decisions, not to confirm an hypothesis that is based on a clinical or physiological basis. A pragmatic trial should aim to be as close as is possible to real-world clinical practices which include the recruitment of participants, setting, design, delivery and implementation of interventions, determining and analysis outcomes, and primary analyses. This is a major distinction between explanatory trials, as described by Schwartz and Lellouch1 which are designed to confirm the hypothesis in a more thorough way.
The most pragmatic trials should not conceal participants or the clinicians. This could lead to bias in the estimations of treatment effects. The trials that are pragmatic should also try to recruit patients from a variety of health care settings, to ensure that the results can be compared to the real world.
Additionally the focus of pragmatic trials should be on outcomes that are important to patients, such as quality of life or functional recovery. This is particularly important when trials involve surgical procedures that are invasive or may have serious adverse impacts. The CRASH trial29, for instance was focused on functional outcomes to compare a two-page report with an electronic system for monitoring of patients admitted to hospitals with chronic heart failure. Similarly, the catheter trial28 focused on urinary tract infections that are symptomatic of catheters as the primary outcome.
In addition to these characteristics pragmatic trials should reduce the procedures for conducting trials and data collection requirements to reduce costs. In the end the aim of pragmatic trials is to make their findings as relevant to real-world clinical practice as is possible. This can be achieved by ensuring that their primary analysis is based on an intention-to treat method (as described in CONSORT extensions).
Despite these requirements however, a large number of RCTs with features that challenge the notion of pragmatism were incorrectly labeled pragmatic and published in journals of all types. This can lead to misleading claims of pragmatism and the usage of the term should be standardised. The development of the PRECIS-2 tool, which offers a standard objective assessment of practical features is a great first step.
Methods
In a practical study the aim is to inform clinical or policy decisions by demonstrating how an intervention can be integrated into routine treatment in real-world contexts. Explanatory trials test hypotheses regarding the causal-effect relationship in idealized conditions. Therefore, pragmatic trials might have less internal validity than explanatory trials, and could be more susceptible to bias in their design, conduct and analysis. Despite their limitations, pragmatic research can provide valuable information for decision-making within the context of healthcare.
The PRECIS-2 tool measures the level of pragmatism that is present in an RCT by scoring it across 9 domains ranging from 1 (very explicative) to 5 (very pragmatic). In this study, the recruit-ment, organization, flexibility in delivery, flexible adherence and follow-up domains received high scores, however, the primary outcome and the method of missing data fell below the practical limit. This indicates that a trial can be designed with well-thought-out practical features, but without harming the quality of the trial.
It is hard to determine the amount of pragmatism in a particular trial because pragmatism does not have a binary characteristic. Some aspects of a research study can be more pragmatic than others. The pragmatism of a trial can be affected by changes to the protocol or logistics during the trial. Koppenaal and colleagues discovered that 36% of the 89 pragmatic studies were placebo-controlled, or conducted prior to the licensing. They also found that the majority were single-center. They aren't in line with the standard practice and are only referred to as pragmatic if their sponsors accept that these trials are not blinded.
A common feature of pragmatic studies is that researchers try to make their findings more meaningful by studying subgroups of the trial sample. This can lead to imbalanced analyses and lower statistical power. This increases the risk of omitting or ignoring differences in the primary outcomes. In the instance of the pragmatic trials included in this meta-analysis this was a serious issue since the secondary outcomes weren't adjusted for the differences in the baseline covariates.
In addition, pragmatic studies may pose challenges to collection and interpretation of safety data. This is due to the fact that adverse events are typically self-reported and are susceptible to delays, errors or coding errors. It is crucial to improve the accuracy and quality of outcomes in these trials.
Results
While the definition of pragmatism does not mean that trials must be 100 percent pragmatic, there are some advantages of including pragmatic elements in clinical trials. These include:
Incorporating routine patients, the results of the trial can be more quickly translated into clinical practice. However, pragmatic trials may be a challenge. For instance, the appropriate type of heterogeneity could help the trial to apply its findings to a variety of settings and patients. However the wrong kind of heterogeneity can reduce assay sensitivity, and thus lessen the ability of a study to detect minor treatment effects.
Several studies have attempted to classify pragmatic trials using a variety of definitions and scoring methods. Schwartz and Lellouch1 have developed an approach to distinguish between explanation-based trials that support a clinical or physiological hypothesis and pragmatic trials that help in the choice of appropriate therapies in real-world clinical practice. The framework consisted of nine domains evaluated on a scale of 1-5 which indicated that 1 was more explanatory while 5 was more practical. The domains included recruitment of intervention, setting up, delivery of intervention, flexible adherence and primary analysis.
The original PRECIS tool3 featured similar domains and scales from 1 to 5. Koppenaal and colleagues10 developed an adaptation of this assessment dubbed the Pragmascope which was more user-friendly to use in systematic reviews. They found that pragmatic systematic reviews had a higher average score in most domains but lower scores in the primary analysis domain.
This difference in the primary analysis domain could be explained by the fact that the majority of pragmatic trials analyse their data in an intention to treat way however some explanation trials do not. The overall score was lower for pragmatic systematic reviews when the domains on the organization, flexibility of delivery and follow-up were merged.
It is crucial to keep in mind that a pragmatic study does not mean that a trial is of poor quality. In fact, there are a growing number of clinical trials that use the word 'pragmatic,' either in their title or abstract (as defined by MEDLINE but which is neither sensitive nor precise). These terms may indicate a greater understanding of pragmatism in abstracts and titles, however it's not clear whether this is reflected in content.
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As the importance of real-world evidence becomes increasingly popular and pragmatic trials have gained popularity in research. They are randomized trials that compare real world treatment options with clinical trials in development. They involve patient populations more closely resembling those treated in regular medical care. This method has the potential to overcome the limitations of observational studies which include the biases that arise from relying on volunteers, and the limited availability and the variability of coding in national registry systems.
Other advantages of pragmatic trials are the possibility of using existing data sources, and a greater chance of detecting meaningful changes than traditional trials. However, these trials could be prone to limitations that compromise their credibility and generalizability. The participation rates in certain trials may be lower than expected due to the health-promoting effect, financial incentives, or competition from other research studies. The requirement to recruit participants in a timely manner also restricts the sample size and the impact of many practical trials. Additionally certain pragmatic trials don't have controls to ensure that the observed differences are not due to biases in trial conduct.
The authors of the Pragmatic Free Trial Meta identified RCTs published from 2022 to 2022 that self-described themselves as pragmatic. They assessed pragmatism using the PRECIS-2 tool, which consists of the domains eligibility criteria, recruitment, flexibility in adherence to interventions, and follow-up. They found that 14 trials scored highly pragmatic or pragmatic (i.e. scoring 5 or higher) in at least one of these domains.
Trials with a high pragmatism rating tend to have higher eligibility criteria than traditional RCTs, which include very specific criteria that are not likely to be found in the clinical environment, and they include populations from a wide range of hospitals. The authors claim that these traits can make pragmatic trials more meaningful and relevant to everyday practice, but they don't necessarily mean that a trial using a pragmatic approach is completely free of bias. In addition, the pragmatism that is present in the trial is not a fixed attribute; a pragmatic trial that doesn't possess all the characteristics of a explanatory trial may yield reliable and relevant results.