Redefining the Hierarchy of Evidence in Medicine in the Era of the Next Generation Clinical Trials and Real World Evidence: A Critical Review and the Next Generation Hierarchy

Innovative evidence modalities—such as OMICS-guided clinical trials, causally interpretable meta-analyses (CMAs), and real-world evidence (RWE)—are increasingly recognized by leading professional organisations and regulatory authorities. A PubMed review revealed gaps in integrating these modalities into the current evidence hierarchies, underscoring the urgent need for a next-generation hierarchy that recognises modern science and regulatory standards. To address this, a new A+ level of evidence is added to the traditional A, B, C hierarchy. Level A+ includes three or more OMICS-guided clinical trials, RCTs, and RWE, supported by multiple secondary evidence reports such as CMAs and/or Systematic Reviews (SRs). Level A includes fewer of these studies ± CMAs and SRs. Level B includes prospective or retrospective studies not meeting the above criteria. Level C includes case reports, laboratory data, expert opinion, and contested studies. Each level is further subdivided into four tiers based on the number and type of clinical reports and the number of secondary evidence available (see text for details). Utilisation of this next-generation hierarchy in clinical practice is expected to streamline the integration of novel evidence into decision-making and facilitate a transparent transition from evidence to guideline recommendations.