The Evolution and Modern Application of the Evidence-Based Medicine Pyramid

The first and earliest principle of evidence-based medicine indicated that a hierarchy of evidence exists. Not all evidence is the same. Today, EBM has defined modern medicine; its goal is to minimise the uncertainties in clinical decision-making and to increase the use of high-quality evidence. In practice, this involves the integration of clinical expertise and patient values with the best available evidence.

The Traditional Hierarchy of Evidence

Evidence-based healthcare practitioners became familiar with this pyramid when reading the literature, applying evidence or teaching students. Various versions of the evidence pyramid have been described, but all of them focused on showing weaker study designs in the bottom (basic science and case series), followed by case–control and cohort studies in the middle, then randomised controlled trials (RCTs), and at the very top, systematic reviews and meta-analysis. Most versions of the pyramid clearly represented a hierarchy of internal validity (risk of bias).

Traditional Hierarchy Levels:

• Top: Systematic reviews and meta-analysis
• High Level: Randomised controlled trials (RCTs)
• Middle Level: Case–control and cohort studies
• Bottom Level: Case series and basic science

The placement of systematic reviews at the top had undergone several alterations in interpretations, but was still thought of as an item in a hierarchy. This description is intuitive and likely correct in many instances. However, some versions incorporated external validity (applicability) in the pyramid by either placing N-1 trials above RCTs or by separating internal and external validity.

Challenges and Visual Modifications

The traditional pyramid was deemed too simplistic at times. Other barriers challenged the placement of systematic reviews and meta-analyses at the top. For instance, heterogeneity (clinical, methodological or statistical) is an inherent limitation of meta-analyses. Additionally, the methodological intricacies and dilemmas of systematic reviews could potentially result in uncertainty and error.

In the early 2000s, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group developed a framework in which the certainty in evidence was based on numerous factors and not solely on study design. Study design alone appears to be insufficient on its own as a surrogate for risk of bias. Therefore, we suggest two visual modifications to the pyramid to illustrate two contemporary methodological principles:

1. Lines separating the study designs become wavy (reflecting GRADE assessments).
2. Systematic reviews are ‘chopped off’ the pyramid.

In this revised view, systematic reviews are a lens through which evidence is viewed and applied.

Evidence Standards during the COVID-19 Pandemic

Coronavirus disease (COVID-19) was declared a pandemic on 11th March 2020. As efforts switched to combat the pandemic, a sharp increase in COVID-19-focused research was observed. However, despite the rapid increase in research, high-quality RCT evidence is limited, with other sources of evidence more readily available.

Adaptation by NICE and Key Agencies

The National Institute of Health and Care Excellence (NICE) has adapted its recommendation process. Utilisation of available evidence is a top priority. The lack of RCT data has necessitated steps to ensure the quality and validity of other sources of evidence, for example real-world data, which has been used to inform COVID-19 NICE guidance. A critical appraisal of evidence, including a risk of bias assessment is required, based on a suitable checklist. For example, the Newcastle-Ottawa scale and the critical appraisal skills programme (CASP) checklist are recommended for appraising non-randomised studies and qualitative studies, respectively.

Furthermore, NICE have been working with the Medicines and Healthcare products Regulatory Agency (MHRA) to rapidly review the safety and efficacy of COVID-19 treatments to produce an evidence summary. For example, NICE have produced a rapid review of remdesivir based on two RCTs and one observational study, which demonstrated a potential clinical benefit in COVID-19 patients.