Consequences of Slow Progress Toward Pragmatism in Randomized Clinical Trials

The randomized clinical trial (RCT) is the gold standard for deriving evidence-based practices in medicine.For common chronic diseases with multifactorial causative mechanisms, the modest treatment effects that can be expected from new therapies usually require randomization to draw a causal inference that observed differences are attributable to the treatment.Despite this, most multisociety cardiovascular disease guidelines rely on inconclusive data from small trials, observational studies, and expert consensus, rather than definitive RCT results; in fact, a recent study found that less than 10% of guideline recommendations are supported by the highest-quality evidence (level of evidence A), which is typically derived from an RCT. 1 In essence, clinicians most often depend on consensus opinion rather than firm evidence for decisions that affect life and death and have a huge effect on quality of life.It is impractical to expect that all day-to-day clinical questions can be answered with traditional RCTs; over time, RCTs have accrued methodologic baggage that is costly and inefficient and does not clearly accomplish the mission of informing decisions.The current designs make recruitment and retention of participants challenging.Furthermore, it is difficult to enroll patients from diverse demographics, and this limits the generalizability of study findings to real-world populations, while much of the process of clinical trials makes limited contribution to answering the questions for which evidence is needed.While most other industries have moved to a much more efficient digital infrastructure, RCTs are mired in traditions that distract from the primary simple concepts that underlie appropriate causal inference: proper randomized treatment assignment, measurement of adherence, and complete ascertainment of critical outcomes.Clinical trialists have developed a construct known as the Pragmatic Explanatory Continuum Indicator Summary (PRECIS), which quantifies the degree to which a trial incorporates pragmatic principles. 2 The updated version of this tool (PRECIS-2) scores 9 elements of trial design: eligibility criteria, recruitment, setting, organization, flexibility (delivery), flexibility (adherence), follow-up, primary outcome, and primary analysis.3 Each element is scored from 1 (very explanatory) to 5 (very pragmatic).In this issue of JAMA Cardiology, Sepehrvand et al 4 use the PRECIS construct to assess how the degree of clinical trial pragmatism has changed in the past 20 years.The authors critically examined cardiovascular disease-associated RCTs published in the top 3 medical and top 3 cardiovascular journals in 2000, 2005, 2010, and 2015.Over time, the degree of pragmatism increased only modestly in the 616 RCTs included; the Related article page 1122Trends in the Explanatory or Pragmatic Nature of Cardiovascular Clinical Trials Over 2 Decades Original Investigation jamacardiology.