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What Is Pragmatic Free Trial Meta? What Are The Benefits And How To Make Use Of It
Recommended Browsing is a free and non-commercial open data platform and infrastructure that supports research on pragmatic trials. It shares clean trial data and ratings using PRECIS-2 allowing for multiple and diverse meta-epidemiological research studies to compare treatment effects estimates across trials that have different levels of pragmatism as well as other design features.

Background

Pragmatic trials are increasingly recognized as providing real-world evidence to support clinical decision-making. The term "pragmatic" however, is not used in a consistent manner and its definition and assessment require further clarification. Pragmatic trials must be designed to inform policy and clinical practice decisions, not to confirm the validity of a clinical or physiological hypothesis. A pragmatic trial should also strive to be as close to real-world clinical practice as possible, such as the participation of participants, setting and design, the delivery and execution of the intervention, and the determination and analysis of the outcomes, and primary analyses. This is a significant difference between explanatory trials, as defined by Schwartz and Lellouch1 that are designed to test the hypothesis in a more thorough manner.


Truely pragmatic trials should not conceal participants or the clinicians. This can lead to an overestimation of the effect of treatment. Pragmatic trials should also seek to recruit patients from a variety of health care settings, to ensure that the results can be compared to the real world.

Finally, pragmatic trials should focus on outcomes that are crucial for patients, such as quality of life or functional recovery. This is particularly relevant for trials involving surgical procedures that are invasive or have potentially dangerous adverse events. The CRASH trial29 compared a two-page report with an electronic monitoring system for patients in hospitals suffering from chronic cardiac failure. The trial with a catheter, on the other hand utilized symptomatic catheter-related urinary tract infection as the primary outcome.

In addition to these aspects, pragmatic trials should minimize the procedures for conducting trials and requirements for data collection to cut down on costs and time commitments. Additionally pragmatic trials should try to make their results as relevant to actual clinical practice as is possible by making sure that their primary method of analysis is the intention-to-treat approach (as described in CONSORT extensions for pragmatic trials).

Despite these criteria however, a large number of RCTs with features that challenge the concept of pragmatism have been mislabeled as pragmatic and published in journals of all kinds. This could lead to misleading claims of pragmatism and the use of the term should be standardized. The creation of the PRECIS-2 tool, which offers an objective standard for assessing pragmatic characteristics is a great first step.

Methods

In a practical trial, the aim is to inform policy or clinical decisions by showing how an intervention could be incorporated into real-world routine care. This is distinct from explanation trials that test hypotheses regarding the cause-effect relationship in idealised settings. Consequently, pragmatic trials may be less reliable than explanatory trials and may 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 measures the degree of pragmatism in an RCT by assessing it on 9 domains ranging from 1 (very explicit) to 5 (very pragmatic). In this study, the areas of recruitment, organisation, flexibility in delivery, flexibility in adherence, and follow-up were awarded high scores. However, the primary outcome and the method for missing data scored below the pragmatic limit. This suggests that it is possible to design a trial using high-quality pragmatic features, without harming the quality of the results.

It is, however, difficult to determine how pragmatic a particular trial is since pragmatism is not a binary quality; certain aspects of a trial may be more pragmatic than others. The pragmatism of a trial can be affected by modifications to the protocol or the logistics during the trial. Koppenaal and colleagues found that 36% of 89 pragmatic studies were placebo-controlled or conducted prior to licensing. Most were also single-center. They are not close to the standard practice, and can only be called pragmatic if their sponsors agree that such trials aren't blinded.

A common aspect of pragmatic research is that researchers try to make their findings more meaningful by studying subgroups within the trial sample. This can result in unbalanced analyses that have less statistical power. This increases the possibility of omitting or ignoring differences in the primary outcomes. In the instance of the pragmatic trials that were included in this meta-analysis this was a significant problem since the secondary outcomes weren't adjusted for differences in baseline covariates.

Furthermore practical trials can be a challenge in the gathering and interpretation of safety data. This is due to the fact that adverse events are usually self-reported and are susceptible to delays in reporting, inaccuracies or coding deviations. It is therefore important to improve the quality of outcome ascertainment in these trials, in particular by using national registries rather than relying on participants to report adverse events in a trial's own database.

Results

While the definition of pragmatism may not require that all clinical trials are 100% pragmatic, there are benefits to including pragmatic components in trials. These include:

By incorporating routine patients, the results of the trial can be more quickly translated into clinical practice. But pragmatic trials can have disadvantages. For instance, the right type of heterogeneity can help a trial to generalise its results to different settings and patients. However the wrong type of heterogeneity can reduce assay sensitivity and therefore lessen the ability of a trial to detect even minor effects of treatment.

Numerous studies have attempted to categorize pragmatic trials with various definitions and scoring systems. Schwartz and Lellouch1 have developed a framework that can differentiate between explanation studies that support the physiological hypothesis or clinical hypothesis, and pragmatic studies that help inform the selection of appropriate treatments in the real-world clinical practice. The framework was comprised of nine domains that were scored on a 1-5 scale, with 1 being more lucid while 5 was more pragmatic. The domains were recruitment setting, setting, intervention delivery, flexible adherence, follow-up and primary analysis.

The initial PRECIS tool3 featured similar domains and a scale of 1 to 5. Koppenaal and colleagues10 developed an adaptation of this assessment, dubbed the Pragmascope that was simpler 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 due to the fact that the majority of pragmatic trials analyse their data in an intention to treat method while some explanation trials do not. The overall score for pragmatic systematic reviews was lower when the areas of organisation, flexible delivery and follow-up were merged.

It is crucial to keep in mind that a pragmatic study does not necessarily mean a low-quality study. In fact, there is an increasing number of clinical trials which use the term "pragmatic" either in their abstracts or titles (as defined by MEDLINE, but that is neither sensitive nor precise). These terms may signal an increased awareness of pragmatism within abstracts and titles, but it's not clear whether this is evident in content.

Conclusions

As appreciation for the value of real-world evidence becomes increasingly commonplace and pragmatic trials have gained traction in research. They are randomized trials that evaluate real-world care alternatives to new treatments that are being developed. They are conducted with populations of patients closer to those treated in regular care. This method is able to overcome the limitations of observational research, like the biases that are associated with the reliance on volunteers, and the lack of coding variations in national registries.

Pragmatic trials also have advantages, including the ability to use existing data sources and a greater likelihood of detecting meaningful differences from traditional trials. However, these trials could be prone to limitations that compromise their validity and generalizability. For example the participation rates in certain 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 limited by the need to recruit participants quickly. In addition, some pragmatic trials lack controls to ensure that the observed differences aren't due to biases in the conduct of trials.

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

Trials with a high pragmatism rating tend to have more expansive eligibility criteria than traditional RCTs which have very specific criteria that aren't likely to be found in the clinical setting, and include populations from a wide range of hospitals. The authors claim that these characteristics could make pragmatic trials more effective and relevant to everyday clinical practice, however they don't necessarily mean that a trial conducted in a pragmatic manner is free from bias. The pragmatism is not a fixed attribute and a test that doesn't have all the characteristics of an explanatory study can still produce valuable and valid results.

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