Large simple randomized controlled trials-from drugs to medical devices: lessons from recent experience

Abstract

Randomized controlled trials (RCTs) are the cornerstone of modern evidence-based medicine. They are considered essential to establish definitive evidence of efficacy and safety for new drugs, and whenever possible they should also be the preferred method for investigating new high-risk medical devices. Well-designed studies robustly inform clinical practice guidelines and decision-making, but administrative obstacles have made it increasingly difficult to conduct informative RCTs. The obstacles are compounded for RCTs of high-risk medical devices by extra costs related to the interventional procedure that is needed to implant the device, challenges with willingness to randomize patients throughout a trial, and difficulties in ensuring proper blinding even with sham procedures. One strategy that may help is to promote the wider use of simpler and more streamlined RCTs using data that are collected routinely during healthcare delivery. Recent large simple RCTs have successfully compared the performance of drugs and of high-risk medical devices, against alternative treatments; they enrolled many patients in a short time, limited costs, and improved efficiency, while also achieving major impact. From a task conducted within the CORE-MD project, we report from our combined experience of designing and conducting large pharmaceutical trials during the COVID-19 pandemic, and of planning and coordinating large registry-based RCTs of cardiovascular devices. We summarize the essential principles and utility of large simple RCTs, likely applicable to all interventions but especially in order to promote their wider adoption to evaluate new medical devices.

Keywords: Large simple trials; Medical devices; Randomized controlled trials.

Fig. 1

Variants of large simple trials. Whether the subject is a volunteer or a patient, and however they qualify for a clinical study or trial, and regardless of the electronic record or computerized database used as the framework for a large simple clinical trial, the essential principles remain the same. The left-hand column shows the common sequential stages of initial assessment and investigation of a patient; the middle column illustrates the types of electronic databases into which data from the subject or patient may be entered at each stage; and the right-hand column lists terminologies commonly applied to trials using those databases. Collectively, these are described as “large, simple trials”

Fig. 2

Impact of the first registry-based randomized trial of a medical device. Illustration of the major impact that was achieved by the first registry-based randomized controlled trial (the TASTE study) [10]. In TASTE, 82% of all potentially eligible patients (in Sweden and Iceland) were enrolled [25]. This figure shows the percentages of all consecutive patients who had ST-elevation myocardial infarction (i.e., not only those enrolled in the trial) who received thrombus aspiration, in different Swedish regions before, during, and after the TASTE trial