Grading system

Natural Standard evidence-based validated grading rationale ™

  • Grades reflect the level of available scientific evidence in support of the efficacy of a given therapy for a specific indication.
  • Expert opinion and folkloric precedent are not included in this assessment, and are reflected in a separate section of each monograph ("Strength of Expert Opinion and Historic / Folkloric Precedent")
  • Evidence of harm is considered separately; the below grades apply only to evidence of benefit.
Level of Evidence Grade Criteria
A (Strong Scientific Evidence) Statistically significant evidence of benefit from >2 properly randomized trials (RCTs), OR evidence from one properly conducted RCT AND one properly conducted meta-analysis, OR evidence from multiple RCTs with a clear majority of the properly conducted trials showing statistically significant evidence of benefit AND with supporting evidence in basic science, animal studies, or theory.
B (Good Scientific Evidence) Statistically significant evidence of benefit from 1-2 properly randomized trials, OR evidence of benefit from >1 properly conducted meta-analysis OR evidence of benefit from >1 cohort/case-control/non-randomized trials AND with supporting evidence in basic science, animal studies, or theory. This grade applies to situations in which a well designed randomized controlled trial reports negative results but stands in contrast to the positive efficacy results of multiple other less well designed trials or a well designed meta-analysis, while awaiting confirmatory evidence from an additional well designed randomized controlled trial.
C (Unclear or Conflicting Scientific Evidence) Evidence of benefit from >1 small RCT(s) without adequate size, power, statistical significance, or quality of design by objective criteria,* OR conflicting evidence from multiple RCTs without a clear majority of the properly conducted trials showing evidence of benefit or ineffectiveness, OR evidence of benefit from >1 cohort/case-control/non-randomized trials AND without supporting evidence in basic science, animal studies, or theory, OR evidence of efficacy only from basic science, animal studies, or theory.
D (Fair Negative Scientific Evidence) Statistically significant negative evidence (i.e., lack of evidence of benefit) from cohort/case-control/non-randomized trials, AND evidence in basic science, animal studies, or theory suggesting a lack of benefit. This grade also applies to situations in which >1 well designed randomized controlled trial reports negative results, notwithstanding the existence of positive efficacy results reported from other less well designed trials or a meta-analysis. (Note: if there is >1 negative randomized controlled trials that are well designed and highly compelling, this will result in a grade of "F" notwithstanding positive results from other less well designed studies.)
F (Strong Negative Scientific Evidence) Statistically significant negative evidence (i.e., lack of evidence of benefit) from >1 properly randomized adequately powered trial(s) of high-quality design by objective criteria.*
Lack of Evidence Unable to evaluate efficacy due to lack of adequate available human data.

*Objective criteria are derived from validated instruments for evaluating study quality, including the 5-point scale developed by Jadad et al., in which a score below 4 is considered to indicate lesser quality methodologically (Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Controlled Clinical Trials 1996; 17[1]:1-12).

† Listed separately in monographs in the "Historical or Theoretical Uses which Lack Sufficient Evidence" section.