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Pragmatic Free Trial Meta
Pragmatic Free Trial Meta is a free and non-commercial open data platform and infrastructure that facilitates research on pragmatic trials. It collects and shares cleaned trial data and ratings using PRECIS-2 allowing for multiple and diverse meta-epidemiological studies that examine the effects of treatment across trials that employ different levels of pragmatism as well as other design features.
Background
Pragmatic studies are increasingly acknowledged as providing evidence from the real world for clinical decision-making. However, the use of the term "pragmatic" is inconsistent and its definition as well as assessment requires further clarification. Pragmatic trials should be designed to guide clinical practice and policy decisions, rather than confirm an hypothesis that is based on a clinical or physiological basis. A pragmatic trial should try to be as close as possible to the real-world clinical practice that include recruitment of participants, setting up, delivery and implementation of interventions, determining and analysis results, as well as primary analysis. This is a major difference between explanatory trials as defined by Schwartz & Lellouch1 which are designed to test the hypothesis in a more thorough way.
Truely pragmatic trials should not conceal participants or the clinicians. This can lead to a bias in the estimates of the effects of treatment. Practical trials should also aim to recruit patients from a wide range of health care settings to ensure that their findings are generalizable to the real world.
Additionally, clinical trials should be focused on outcomes that matter to patients, like quality of life and functional recovery. This is especially important in trials that involve invasive procedures or those with potentially dangerous adverse events. The CRASH trial29 compared a two-page report with an electronic monitoring system for hospitalized patients with chronic heart failure. The catheter trial28 however was based on symptomatic catheter-related urinary tract infection as its primary outcome.
In addition to these features pragmatic trials should reduce the trial's procedures and data collection requirements in order to reduce costs. In the end the aim of pragmatic trials is to make their results as relevant to actual 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 within CONSORT extensions).
Many RCTs which do not meet the requirements for pragmatism however, they have characteristics that are in opposition to pragmatism, have been published in journals of different types and incorrectly labeled as pragmatic. This could lead to false claims about pragmatism, and the term's use should be standardized. The creation of the PRECIS-2 tool, which offers an objective standard for assessing pragmatic features is a great first step.
Methods
In a pragmatic research study it is the intention to inform clinical or policy decisions by demonstrating how an intervention can be integrated into routine treatment in real-world situations. Explanatory trials test hypotheses concerning the cause-effect relationship within idealised settings. In this way, pragmatic trials can have lower internal validity than studies that explain and be more susceptible to biases in their design analysis, conduct, and design. Despite these limitations, pragmatic trials can provide valuable information to decision-making in healthcare.
The PRECIS-2 tool evaluates an RCT on 9 domains, ranging between 1 and 5 (very pragmatist). In this study, the areas of recruitment, organization and flexibility in delivery, flexible adherence, and follow-up were awarded high scores. However, 프라그마틱 플레이 and the method of missing data scored below the pragmatic limit. This suggests that a trial could be designed with good practical features, yet not damaging the quality.
However, it's difficult to assess how practical a particular trial is since the pragmatism score is not a binary attribute; some aspects of a trial can be more pragmatic than others. A trial's pragmatism could be affected by changes to the protocol or logistics during the trial. Koppenaal and colleagues found 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. This means that they are not quite as typical and can only be called pragmatic when their sponsors are accepting of the lack of blinding in these trials.
A common aspect of pragmatic studies is that researchers try to make their findings more meaningful by studying subgroups of the trial sample. However, this can lead to unbalanced results and lower statistical power, thereby increasing the likelihood of missing or misinterpreting differences in the primary outcome. In the case of the pragmatic studies included in this meta-analysis this was a major issue because the secondary outcomes were not adjusted to account for the differences in baseline covariates.
Additionally the pragmatic trials may be a challenge in the collection and interpretation of safety data. It is because adverse events tend to be self-reported and are susceptible to delays, errors or coding differences. It is therefore crucial to improve the quality of outcomes for these trials, and 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 doesn't require that all clinical trials are 100% pragmatic there are benefits of including pragmatic elements in trials. These include:
Incorporating routine patients, the results of trials can be translated more quickly into clinical practice. However, pragmatic studies can also have drawbacks. For instance, the appropriate type of heterogeneity can help a trial to generalise its results to many different settings and patients. However, the wrong type of heterogeneity can reduce assay sensitivity and therefore reduce the power of a study to detect minor treatment effects.
Many studies have attempted classify pragmatic trials using a variety of definitions and scoring methods. Schwartz and Lellouch1 developed a framework to distinguish between explanatory studies that support a physiological hypothesis or clinical hypothesis, and pragmatic studies that inform the selection of appropriate therapies in real world clinical practice. The framework was composed of nine domains evaluated on a scale of 1-5 which indicated that 1 was more explanatory while 5 being more pragmatic. The domains included recruitment of intervention, setting up, delivery of intervention, flexible adhering to the program and primary analysis.
The initial PRECIS tool3 had similar domains and scales from 1 to 5. Koppenaal and colleagues10 created an adaptation of the assessment, dubbed the Pragmascope, that was easier to use for systematic reviews. They discovered that pragmatic systematic reviews had higher average scores in the majority of domains, with lower scores in the primary analysis domain.
This distinction in the primary analysis domain can be due to the way in which most pragmatic trials approach data. Certain explanatory trials however, do not. The overall score was lower for pragmatic systematic reviews when the domains of the organization, flexibility of delivery and follow-up were merged.
It is important to remember that a pragmatic trial doesn't necessarily mean a poor quality trial, and in fact there is an increasing rate of clinical trials (as defined by MEDLINE search, however this is not specific or sensitive) that use the term "pragmatic" in their abstracts or titles. The use of these words in abstracts and titles could suggest a greater awareness of the importance of pragmatism, but it is unclear whether this is evident in the content of the articles.
Conclusions
As the importance of evidence from the real world becomes more popular the pragmatic trial has gained momentum in research. They are randomized trials that compare real world treatment options with clinical trials in development. They are conducted with populations of patients closer to those treated in regular medical care. This method can help overcome limitations of observational studies which include the biases that arise from relying on volunteers and limited availability and the variability of coding in national registry systems.
Other benefits of pragmatic trials include the ability to use existing data sources, and a greater probability of detecting significant changes than traditional trials. However, they may have some limitations that limit their reliability and generalizability. For example the rates of participation in some trials might be lower than expected due to the healthy-volunteer effect as well as financial incentives or competition for participants from other research studies (e.g., industry trials). Practical trials are often restricted by the necessity to enroll participants on time. Practical trials aren't always equipped with controls to ensure that the observed differences aren't due to biases during the trial.
The authors of the Pragmatic Free Trial Meta identified 48 RCTs self-labeled as pragmatic and that were published until 2022. They assessed pragmatism using the PRECIS-2 tool that 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. scoring 5 or more) in any one or more of these domains, and that the majority of them were single-center.
Trials with a high pragmatism score tend to have more expansive eligibility criteria than traditional RCTs, which include very specific criteria that aren't likely to be found in the clinical setting, and comprise patients from a wide range of hospitals. The authors argue that these characteristics could make pragmatic trials more effective and relevant to daily practice, but they do not necessarily guarantee that a pragmatic trial is free from bias. In addition, the pragmatism that is present in trials is not a fixed attribute and a pragmatic trial that doesn't possess all the characteristics of an explanatory trial can produce reliable and relevant results.