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

A  (Strong Scientific Evidence)

B  (Good Scientific Evidence)

C  (Unclear or Conflicting
       Scientific Evidence)

D  (Fair Negative
       Scientific Evidence)

F  (Strong Negative
       Scientific Evidence)

Lack of Evidence†

Criteria

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.

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.

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.

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.)

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.*

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.