All Times EDT
It is healthy to periodically question the things that we have long taken for granted. Although randomized clinical trials are the gold standard for evaluating the benefits and harms of interventions, they fail to provide the necessary evidence to inform practical medical decision-making. The primary reason for this is failure to recognize the most important questions for treating patients.
Many of our modern pursuits appear to be driven by the desire to save resources and time, motivations magnified by business, political, and academic pressures. Though understandable, such desires can be dangerous threatening our objectivity and ability to reason, resulting in studies with lower integrity, reproducibility, and applicability. Modern ideas include: conducting observational rather than randomized studies rationalized by the increasing access to real world data and the belief that modeling can replace randomization, using surrogate rather than clinical outcomes, using surrogate rather than clinical populations, using per protocol analyses instead of ITT, and using assumptions regarding treatment effects in place of data for estimating those effects. These trends are often labeled “innovative”. However are these progressions…. or regressions… fancy ways of lowering the usual evidentiary standard and introducing greater uncertainty? Many appear to be a willingness to make additional assumptions, prioritizing speed and resource efficiency at the expense of robustness, objectivity, and scientific rigor.
Traditional approaches are in need in improvements. For example, standard approaches synthesizing information obtained from separate analysis of each outcome fail to incorporate associations between outcomes and recognize the cumulative nature of outcomes in individual patients, suffer from competing risk complexities during interpretation, and since efficacy and safety analyses are often conducted on different populations, generalizability is unclear.
Can we redirect our motivation to find BETTER answers to the most important questions for patients and clinicians? Though often misunderstood, one such opportunity is pragmatism, the concept of truly getting closer to understanding the effects of interventions as experienced by patients. I propose that we place increased interest on questions of a pragmatic origin to match their clinical importance and real-world utility. Ideas for adjustments to trial design, conduct, and analyses that allow for answering the most important questions for medical-decision making are discussed.