A randomised controlled trial (RCT) is an experiment designed by investigators to study the efficacy and safety of at least two interventions in groups of randomly assigned subjects. The main value of randomisation is that the study groups are designed to be as near identical as possible in measured as well as unmeasured characteristics that may impact on the study outcomes. Where possible (more likely when medicines are compared) patients, investigators and assessors are ‘blinded’ as to which subjects are receiving which intervention. Patients (study subjects) are recruited using pre-specified inclusion and exclusion criteria, and following a review of the study protocol and agreement for the study to proceed by an independent ethical committee. The study protocol describes all aspects of the study, including the trial duration and schedule of visits: usually multiple follow-ups to measure the outcomes of interest. When the follow-up schedule is completed for the final study subject, the ‘blind’ is broken, and analysis comparing the study groups is undertaken, using statistical methods pre-specified in an analysis plan, with a pre-specified criterion for success. Success usually consists of rejection of a ‘null’ hypothesis – i.e. no difference between treatment groups in the outcome measure. The null hypothesis together with the expected population variation in the outcome measure is used to power the trial and calculate the required sample size. Study groups should be analysed according to ‘intention to treat’, in which subjects are allocated to the group to which they were randomised (whatever happens next). ‘On treatment’ analyses, which take into account any withdrawals or cross-overs between treatment groups during the trial, may also be useful. During the trial an independent panel reviews the blinded data to identify unexpectedly large (or small) differences in efficacy or safety between groups that may require the trial to be terminated early on ethical grounds. RCTs are considered very important evidence in the development of any medical intervention, and their results are frequently identified in systematic reviews and meta-analyses and are used in health economic modelling. An important distinction is made between ‘explanatory’ trials, which use very tight protocols and intense follow-up to measure safety and efficacy with the minimal possible opportunity for bias, and pragmatic trials in which the aim is to mimic usual practice with broader inclusion criteria and fewer protocol-related activities (and so generate results which may be considered more generalizable to routine practice).
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