Abstract
Randomized controlled trials (RCTs) are conducted under idealized and rigorously controlled conditions that may compromise their external validity. A literature review was conducted of published English language articles that reported the findings of studies assessing external validity by a comparison of the patient sample included in RCTs reporting on pharmaceutical interventions with patients from everyday clinical practice. The review focused on publications in the fields of cardiology, mental health, and oncology. A range of databases were interrogated (MEDLINE; EMBASE; Science Citation Index; Cochrane Methodology Register). Double-abstract review and data extraction were performed as per protocol specifications. Out of 5,456 de-duplicated abstracts, 52 studies met the inclusion criteria (cardiology, n = 20; mental health, n = 17; oncology, n = 15). Studies either performed an analysis of the baseline characteristics (demographic, socioeconomic, and clinical parameters) of RCT-enrolled patients compared with a real-world population, or assessed the proportion of real-world patients who would have been eligible for RCT inclusion following the application of RCT inclusion/exclusion criteria. Many of the included studies concluded that RCT samples are highly selected and have a lower risk profile than real-world populations, with the frequent exclusion of elderly patients and patients with co-morbidities. Calculation of ineligibility rates in individual studies showed that a high proportion of the general disease population was often excluded from trials. The majority of studies (n = 37 [71.2 %]) explicitly concluded that RCT samples were not broadly representative of real-world patients and that this may limit the external validity of the RCT. Authors made a number of recommendations to improve external validity. Findings from this review indicate that there is a need to improve the external validity of RCTs such that physicians treating patients in real-world settings have the appropriate evidence on which to base their clinical decisions. This goal could be achieved by trial design modification to include a more representative patient sample and by supplementing RCT evidence with data generated from observational studies. In general, a thoughtful approach to clinical evidence generation is required in which the trade-offs between internal and external validity are considered in a holistic and balanced manner.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-015-1023-4) contains supplementary material, which is available to authorized users.
Highlights
Designed and executed randomized controlled trials (RCTs) represent the current gold-standard primary study design for the determination of the efficacy and safety of medical interventions [1]
The present analysis utilized a robust literature review methodology to identify studies that compared the clinical characteristics of an RCT sample and patients from a realworld source (Method A) or assessed the proportion of a real-world population that would satisfy criteria for RCT inclusion (Method B). Publications identified by this methodology indicated that RCT samples in cardiology, mental health, and oncology studies that assessed pharmaceutical interventions in adult patients were often not broadly representative of patients treated in everyday clinical practice and that caution should be exercised when extrapolating data from trials to patients treated in usual care settings
In the majority of studies included in this literature review it was concluded that patient samples in cardiology, mental health, and oncology RCTs are not broadly representative of patients encountered in everyday practice
Summary
Designed and executed randomized controlled trials (RCTs) represent the current gold-standard primary study design for the determination of the efficacy and safety of medical interventions [1]. Explanatory RCTs are designed to determine the efficacy of an intervention under idealized and controlled circumstances and so are conducted under rigorous conditions, including strict adherence to structured protocols, the use of restrictive inclusion and exclusion criteria, and patient randomization, that maximize their internal validity (that is to ensure they minimize the possibility of bias regarding the effect of an intervention) [3, 4]. As it is challenging to simultaneously optimize internal and external validity, efficacy data from traditional explanatory RCTs are often complemented by evidence from pragmatic trials (including pragmatic RCTs) or observational studies that determine the performance of an intervention under conditions more closely resembling routine clinical practice, and include more heterogeneous patient populations and less stringent treatment and delivery protocols [4]. Evidence from all these sources can be complementary in understanding the effect of an intervention and furthering clinical research [8]
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