Pragmatic Free Trial Meta
Pragmatic Free Trail Meta is an open data platform that allows research into pragmatic trials. It collects and distributes cleaned trial data, ratings, and evaluations using PRECIS-2. This allows for diverse meta-epidemiological analyses that evaluate the effects of treatment across trials of various levels of pragmatism.
Background
Pragmatic studies provide real-world evidence that can be used to make clinical decisions. The term "pragmatic" however, is not used in a consistent manner and its definition and measurement need further clarification. The purpose of pragmatic trials is to inform policy and clinical practice 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 actual clinical practices which include the recruitment of participants, setting, design, delivery and implementation of interventions, determining and analysis results, as well as primary analyses. This is a major difference between explanation-based trials, as described by Schwartz & Lellouch1, which are designed to confirm a hypothesis in a more thorough way.
The most pragmatic trials should not blind participants or the clinicians. This can lead to a bias in the estimates of treatment effects. Pragmatic trials will also recruit patients from various healthcare settings to ensure that the outcomes can be compared to the real world.
Finally, pragmatic trials must be focused on outcomes that matter to patients, such as quality of life and functional recovery. This is particularly relevant in trials that require the use of invasive procedures or could have serious adverse impacts. The CRASH trial29, for example was focused on functional outcomes to compare a two-page report with an electronic system for the monitoring of patients admitted to hospitals with chronic heart failure. Similarly, the catheter trial28 utilized symptomatic catheter-associated urinary tract infections as the primary outcome.
In addition to these characteristics the pragmatic trial should also reduce the trial's procedures and data collection requirements in order to reduce costs. Finaly the aim of pragmatic trials is to make their findings as relevant to actual clinical practice as is possible. This can be accomplished by ensuring that their analysis is based on an intention-to treat method (as described within CONSORT extensions).
Many RCTs which do not meet the criteria for pragmatism, however, they have characteristics that are contrary to pragmatism, have been published in journals of varying types and incorrectly labeled pragmatic. This can lead to misleading claims about pragmatism, and the use of the term should be standardized. The creation of a PRECIS-2 tool that can provide an objective and standardized evaluation of pragmatic aspects is the first step.
Methods
In a pragmatic study the goal is to inform clinical or policy decisions by demonstrating how an intervention would be implemented into routine care. This differs from explanation trials that test hypotheses about the cause-effect connection in idealized settings. Consequently, pragmatic trials may 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 provide valuable information to decisions in the context of healthcare.
The PRECIS-2 tool measures the level of pragmatism that is present in an RCT by assessing it on 9 domains that range from 1 (very explanatory) to 5 (very pragmatic). In this study, the recruit-ment organization, flexibility in delivery, flexible adherence and follow-up domains were awarded high scores, but the primary outcome and the procedure for missing data fell below the limit of practicality. This suggests that it is possible to design a trial using excellent pragmatic features without compromising the quality of its outcomes.
It is difficult to determine the degree of pragmatism in a particular trial since pragmatism doesn't have a binary characteristic. Certain aspects of a study may be more pragmatic than other. Furthermore, logistical or protocol modifications made during a trial can change its pragmatism score. In addition 36% of the 89 pragmatic trials discovered by Koppenaal and colleagues were placebo-controlled, or conducted prior to licensing, and the majority were single-center. Thus, they are not quite as typical and can only be called pragmatic in the event that their sponsors are supportive of the lack of blinding in these trials.
Furthermore, a common feature of pragmatic trials is that the researchers try to make their results more valuable by studying subgroups of the trial sample. This can lead to imbalanced analyses and less statistical power. This increases the risk of omitting or ignoring differences in the primary outcomes. In the case of the pragmatic trials included in this meta-analysis this was a significant problem since the secondary outcomes were not adjusted to account for the differences in baseline covariates.
Furthermore the pragmatic trials may present challenges in the collection and interpretation of safety data. It is because adverse events tend to be self-reported and are susceptible to errors, delays or coding errors. Therefore, it is crucial to improve the quality of outcomes for these trials, ideally by using national registries instead of relying on participants to report adverse events on a trial's own database.
Results
While the definition of pragmatism may not require that all trials are 100 percent pragmatic, there are advantages to incorporating pragmatic components into clinical trials. These include:
By including routine patients, the results of trials can be more quickly translated into clinical practice. However, pragmatic trials may have their disadvantages. For instance, the right kind of heterogeneity can allow the trial to apply its results to different patients and settings; however the wrong type of heterogeneity can reduce assay sensitiveness and consequently reduce the power of a trial to detect small treatment effects.
A number of studies have attempted to classify pragmatic trials with a variety of definitions and scoring systems. Schwartz and Lellouch1 created a framework to differentiate between explanation studies that support the physiological hypothesis or clinical hypothesis, and pragmatic studies that help inform the selection of appropriate therapies in the real-world clinical practice. The framework consisted of nine domains that were scored on a 1-5 scale with 1 being more explanatory while 5 was more pragmatic. The domains were recruitment and setting, delivery of intervention with flexibility, follow-up and primary analysis.
The original PRECIS tool3 was based on a similar scale and domains. Koppenaal et al10 devised an adaptation of this assessment called the Pragmascope that was easier to use in systematic reviews. They discovered that pragmatic systematic reviews had higher average scores across all domains, with lower scores in the primary analysis domain.
This difference in the main analysis domain could be due to the fact that most pragmatic trials analyse their data in an intention to treat manner, whereas some explanatory trials do not. The overall score for systematic reviews that were pragmatic was lower when the areas of management, flexible delivery and following-up were combined.
It is crucial to keep in mind that a pragmatic study does not mean that a trial is of poor quality. In fact, there is an increasing number of clinical trials that employ the term 'pragmatic' either in their abstracts or titles (as defined by MEDLINE, but that is neither precise nor sensitive). The use of these words in abstracts and titles could indicate a greater understanding of the importance of pragmatism, but it is unclear whether this is evident in the content of the articles.
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As the importance of evidence from the real world becomes more widespread, pragmatic trials have gained momentum in research. They are randomized trials that evaluate real-world care alternatives to clinical trials in development. They are conducted with populations of patients closer to those treated in regular medical care. This method can help overcome the limitations of observational research like the biases associated with the use of volunteers and the limited availability and the coding differences in national registry.
Pragmatic trials have other advantages, including the ability to draw on existing data sources and a greater probability of detecting meaningful differences than traditional trials. However, pragmatic tests may be prone to limitations that undermine their effectiveness and generalizability. For example, participation rates in some trials may be lower than anticipated due to the healthy-volunteer influence and incentives to pay or compete for participants from other research studies (e.g. industry trials). The necessity to recruit people quickly restricts the sample size and the impact of many pragmatic trials. Some pragmatic trials also lack controls to ensure that the observed variations aren't due to biases that occur during the trial.
The authors of the Pragmatic Free Trial Meta identified 48 RCTs that self-labeled themselves as pragmatic and that were published up to 2022. They evaluated pragmatism using the PRECIS-2 tool, which includes the eligibility criteria for domains and recruitment criteria, as well as flexibility in intervention adherence, and follow-up. They found that 14 of these trials scored pragmatic or highly practical (i.e. scores of 5 or higher) in any one or more of these domains, and that the majority of these were single-center.
Trials with a high pragmatism rating tend to have more expansive eligibility criteria than traditional RCTs that have specific criteria that aren't likely to be present in the clinical environment, and they comprise patients from a wide range of hospitals. The authors suggest that these characteristics can help make pragmatic trials more effective and applicable to daily practice, but they do not guarantee that a pragmatic trial is free of bias. In addition, the pragmatism that is present in a trial is not a definite characteristic A pragmatic trial that doesn't possess all the characteristics of an explanatory trial can produce reliable and relevant results.