Large simple trials: really, it can't be that simple!

Abstract

In this issue of the European Heart Journal , Calvo et al. 1 present another plea for simplified approaches to clinical trials evaluating cardiovascular therapies. In the interest of disclosure, I note that I work closely with many of the authors of this article. Dr Christopher Granger, in particular, is a long-time collaborator and senior investigator in my own institution. The thesis advanced by Calvo et al. could be called the ‘large simple trial (LST) mantra’. Although I agree with most of the concepts expressed in their paper—and indeed, I co-chair the Clinical Trials Transformation Initiative (http://www.ctti-clinicaltrials.org/), a public-private partnership with the US Food and Drug Administration (FDA), and more than 60 other organizations that champion similar ideas—this mantra nonetheless omits important aspects that should be considered if LSTs are to be understood within a larger context. To clarify the role that LSTs can play in informing the cardiovascular evidence base, I believe that the following issues deserve consideration. A recent analysis of data from the ClinicalTrials.gov registry showed that only 3–4% of interventional trials enrol more than 5000 participants, while the vast majority—over 90%—enrol fewer than 100 participants2 and therefore could not possibly apply LST methods. Numerous articles published in the nearly three decades since Yusuf, Collins, and Peto first advocated this approach3 have touted LST methods, including the streamlining of trial designs and focusing on outcomes that matter to patients, but these key details have largely gone unheeded. LSTs are vastly outnumbered by complex trials, both large and small. Accordingly, the overwhelming majority of trials do not inform the decisions that patients, healthcare providers, and health systems must make every day, and the overall cost of trials continues to escalate while proliferating bureaucracies absorb ever-increasing shares of research budgets. Thus, a reasonable goal would be to …