Abstract
Randomized clinical trials often serve the purpose of assessing the efficacy and safety of a compound. By combining real-world evidence and randomization, pragmatic randomized clinical trials (PrCTs) can be used to inform treatment effectiveness and healthcare decisions. PrCTs, referring to studies where several pragmatic elements are used (eligibility, endpoints, follow-up, etc.), pose unique challenges (Loudon et al. in BMJ 350:h2147, 2015). From a literature review, we propose a definition of PrCT and discuss strategies to overcome some PrCT challenges. Use of alternative data collection approaches may lead to uncertainties, and absence of blinding could potentially lead to non-random missing data at study endpoints such that randomization is no longer protected by an intent to treat. Therefore, more complex randomization strategies may be needed to minimize bias. Additional data sources could be used to synthesize information and create a more accurate endpoint definition, which may require tools such as natural language processing. The statistician must become familiar with the challenges and strengths of PrCTs, ranging from design to analysis to interpretation, in order to transform data into evidence (Califf in Clin Trials 13:471–477, 2016).
Highlights
Classical randomized clinical trials (RCTs), especially Phase III trials, are planned with the intent to show efficacy and safety of a new compound
Differing from classical RCTs, pragmatic trials answer the important question of the effectiveness of a therapy in the “real world,” rather than efficacy in a pre-specified patient population
One of the main advantages in conducting Pragmatic randomized clinical trials (PrCTs) is the importance of the use of randomization, which cannot be implemented in real-world observational studies
Summary
Classical randomized clinical trials (RCTs), especially Phase III trials, are planned with the intent to show efficacy and safety of a new compound. The sites contributing are mainly specialized clinical research study sites Often, these sites have been running trials for several years, have staff with extensive clinical trial experience, and are familiar with the processes involved in running such studies, from patient recruitment, informed consent, ensuring regular visit schedules, up to correct data collection [with standard electronic case report forms (eCRFs), or even via personal devices such as ambulatory blood pressure measurement monitors]. Pragmatic randomized clinical trials (PrCTs) are conducted to answer the important question of how a treatment works in a “real-world scenario,” a heterogeneous “realworld population,” in short to estimate the treatment’s effectiveness. We discuss PrCT definitions in the literature, propose a broad definition anchored on concepts used by others (including Hotopf 2002; MacPherson 2004; Zuidgeest et al 2017; the CONSORT statement updated for pragmatic studies (Zwarenstein et al 2008); and the PRECIS tool (Thorpe et al 2009)], and highlight several statistical challenges with potential solutions
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