Pragmatic Free Trial Meta

Pragmatic Free Trial Meta is a non-commercial, open data platform and infrastructure that facilitates research on pragmatic trials. It shares clean trial data and ratings using PRECIS-2, which allows for multiple and varied meta-epidemiological studies to evaluate the effect of treatment on trials that employ different levels of pragmatism as well as other design features.

Background

Pragmatic trials provide evidence from the real world that can be used to make clinical decisions. The term "pragmatic", however, is not used in a consistent manner and its definition and measurement require further clarification. Pragmatic trials are designed to guide clinical practices and policy choices, rather than confirm a physiological hypothesis or clinical hypothesis. A pragmatic trial should try to be as close as it is to real-world clinical practices that include recruiting participants, setting, design, delivery and implementation of interventions, determination and analysis results, as well as primary analyses. This is a major difference between explanatory trials, as defined by Schwartz and Lellouch1, which are designed to confirm a hypothesis in a more thorough way.

Studies that are truly pragmatic must be careful not to blind patients or healthcare professionals as this could result in bias in estimates of treatment effects. Pragmatic trials should also seek to attract patients from a wide range of health care settings so that their results can be compared to the real world.

Finally, pragmatic trials must concentrate on outcomes that are important to patients, like quality of life and functional recovery. This is particularly important in trials that require surgical procedures that are invasive or may have serious adverse consequences. The CRASH trial29, for example was focused on functional outcomes to compare a two-page report with an electronic system for monitoring of hospitalized patients with chronic heart failure. In addition, the catheter trial28 focused on urinary tract infections caused by catheters as the primary outcome.

In addition to these characteristics pragmatic trials should also reduce trial procedures and data-collection requirements to cut costs and time commitments. Furthermore pragmatic trials should strive to make their findings as relevant to actual clinical practice as possible by making sure that their primary method of analysis follows the intention-to treat approach (as described in CONSORT extensions for pragmatic trials).

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 kinds. This can lead to false claims of pragmaticity, and the usage of the term must be standardized. The development of the PRECIS-2 tool, which offers a standard objective assessment of pragmatic characteristics is a great first step.

Methods

In a pragmatic study it is the intention to inform policy or clinical decisions by demonstrating how the intervention can be implemented into routine care. This is distinct from explanation trials that test hypotheses regarding the cause-effect relationship in idealised settings. 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 these limitations, pragmatic trials may be a valuable source of information for decision-making in the context of healthcare.

The PRECIS-2 tool assesses the degree of pragmatism within an RCT by assessing it across 9 domains that range from 1 (very explicit) to 5 (very pragmatic). In this study, the recruit-ment, organisation, flexibility: delivery and follow-up domains scored high scores, however the primary outcome and the method for missing data were below the practical limit. This suggests that it is possible to design a trial with excellent pragmatic features without damaging the quality of its results.

It is hard to determine the degree of pragmatism within a specific study because pragmatism is not a have a single attribute. Some aspects of a study may be more pragmatic than others. A trial's pragmatism can be affected by changes to the protocol or logistics during the trial. In addition 36% of the 89 pragmatic trials discovered by Koppenaal and colleagues were placebo-controlled, or conducted prior to licensing and most were single-center. Therefore, they aren't as common and can only be described as pragmatic when their sponsors are accepting of the absence of blinding in these trials.

Additionally, a typical feature of pragmatic trials is that the researchers try to make their results more valuable by studying subgroups of the sample. However, this can lead to unbalanced comparisons with a lower statistical power, thereby increasing the likelihood of missing or incorrectly detecting differences in the primary outcome. In the case of the pragmatic trials that were included in this meta-analysis this was a serious issue because the secondary outcomes were not adjusted to account for the differences in the baseline covariates.

Additionally, studies that are pragmatic can present challenges in the gathering and interpretation of safety data. It is because adverse events tend to be self-reported, and therefore are prone to errors, delays or coding differences. It is essential to increase the accuracy and quality of outcomes in these trials.

Results

While the definition of pragmatism may not require that all trials be 100% pragmatic, there are some advantages of including pragmatic elements in clinical trials. These include:

By including routine patients, the trial results are more easily translated into clinical practice. However, pragmatic trials may be a challenge. The right kind of heterogeneity, for example could help a study generalise its findings to many different patients or settings. However the wrong type of heterogeneity could reduce the sensitivity of an assay and, consequently, decrease the ability of a study to detect small treatment effects.

A variety of studies have attempted to classify pragmatic trials using various definitions and scoring systems. Schwartz and Lellouch1 developed a framework for distinguishing between explanatory trials that confirm the clinical or physiological hypothesis as well as pragmatic trials that aid in the choice of appropriate therapies in real-world clinical practice. Their framework included nine domains that were scored on a scale ranging from 1-5, with 1 being more informative and 5 indicating more pragmatic. The domains were recruitment and setting, delivery of intervention, flexible adherence, follow-up and primary analysis.

The initial PRECIS tool3 included similar domains and an assessment scale ranging from 1 to 5. Koppenaal et al10 devised an adaptation to this assessment called the Pragmascope that was easier to use in systematic reviews. They found that pragmatic systematic reviews had higher average scores across all domains but lower scores in the primary analysis domain.

The difference in the analysis domain that is primary could be explained by the fact that the majority of pragmatic trials process their data in the intention to treat manner, whereas some explanatory trials do not. The overall score was lower for pragmatic systematic reviews when the domains of the organization, flexibility of delivery and follow-up were combined.

It is important to remember that a study that is pragmatic does not mean a low-quality trial. In fact, there are an increasing number of clinical trials that use the term "pragmatic" either in their abstract or title (as defined by MEDLINE, but that is neither precise nor sensitive). The use of these words in abstracts and titles may suggest a greater awareness of the importance of pragmatism but it is unclear whether this is evident in the contents of the articles.

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In recent times, pragmatic trials are becoming more popular in research as the importance of real-world evidence is becoming increasingly acknowledged. They are randomized studies that compare real-world care alternatives to experimental treatments in development. They include patient populations closer to those treated in regular medical care. This approach could help overcome limitations of observational studies which include the biases that arise from relying on volunteers and limited accessibility and coding flexibility in national registry systems.

Pragmatic trials have other advantages, like the ability to use existing data sources and a greater chance of detecting significant differences than traditional trials. However, these tests could still have limitations which undermine their validity and generalizability. For example the rates of participation in some trials may be lower than anticipated due to the healthy-volunteer effect and financial incentives or competition for participants from other research studies (e.g. industry trials). A lot of pragmatic trials are restricted by the need to recruit participants on time. In addition, some pragmatic trials lack controls to ensure that the observed differences are not due to biases in the conduct of trials.

The authors of the Pragmatic Free Trial Meta identified 48 RCTs that self-labeled themselves as pragmatic and were published from 2022. The PRECIS-2 tool was employed to assess the pragmatism of these trials. It covers domains such as eligibility criteria and flexibility in recruitment and adherence to intervention and follow-up. They discovered that 14 of the trials scored highly or pragmatic pragmatic (i.e. scores of 5 or higher) in one or more of these domains and that the majority of these were single-center.

Studies that have high pragmatism scores tend to have more criteria for eligibility than conventional RCTs. They also contain populations from various hospitals. The authors claim that these characteristics could make the pragmatic trials more relevant and applicable to everyday practice, but they don't necessarily mean that a pragmatic trial is completely free of bias. Moreover, the pragmatism of trials is not a definite characteristic and a pragmatic trial that does not possess all the characteristics of a explanatory trial can yield valid and useful results.