Beginning in the 1970s and 1980s, the emergence of randomized clinical trials and studies with large cohorts, associated with the development of the methodology for systematic reviews and meta-analyses, triggered a revolution in the way of thinking and performing healthcare practice. Evidence-based medicine (EBM), defined as the integration of the best research evidence with clinical experience and patient values, has become a new paradigm, orienting medical education and specialized publications. One of the principles of EBM was precisely the primacy of information obtained from randomized clinical trials and meta-analyses, which were placed at the top of an evidence hierarchy, valuing quantitative results more than clinical experience and expert opinion. Indeed, it has always been challenging for EBM to integrate empirical evidence with other types of medical knowledge, such as clinical expertise and pathophysiological rationale, or even with the preferences of individual patients.

The use of EBM in clinical practice also runs into the difficulty of finding robust evidence for all subgroups of clinical situations found in the real world, “gray areas” in which no reliable evidence can be obtained from the scientific literature to guide the physician in caring for his patient. Randomized clinical trials are expensive and generally require large study samples and long-term follow-up. There are several situations without evidence, or situations in which the evidence is inconsistent or of poor quality.

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