|
Grade of recommendation |
Level of Evidence |
Therapy: Whether a treatment is efficacious/ effective/harmful |
Therapy: Whether a drug is superior to another drug in its same class |
Prognosis |
Diagnosis |
Differential diagnosis/symptom prevalence study |
Economic and decision analysis |
|
A |
1a |
SR (with homogeneity*) of RCTs |
SR (with homogeneity**) of head-to-head RCTs |
SR (with homogeneity*) of inception cohort studies; CDR† validated in different populations |
SR (with homogeneity*) of Level 1 diagnostic studies; CDR† with 1b studies from different clinical centres |
SR (with homogeneity*) of prospective cohort studies |
SR (with homogeneity*) of Level 1 economic studies |
|
1b |
Individual RCT (with narrow Confidence Interval‡) |
Within a head-to-head RCT with clinically important outcomes |
Individual inception cohort study with > 80% follow-up; CDR† validated in a single population |
Validating** cohort study with good††† reference standards; or CDR† tested within one clinical centre |
Prospective cohort study with good follow-up**** |
Analysis based on clinically sensible costs or alternatives; systematic review(s) of the evidence; and including multi-way sensitivity analyses | |
|
1c |
All or none case-series |
All or none case-series |
|||||
| B |
2a |
SR (with homogeneity*) of cohort studies |
Within a head-to-head RCT with validated surrogate outcomes ‡‡‡ |
SR (with homogeneity*) of either retrospective cohort studies or untreated control groups in RCTs |
SR (with homogeneity*) of Level >2 diagnostic studies |
SR (with homogeneity*) of 2b and better studies |
SR (with homogeneity*) of Level >2 economic studies |
|
2b |
Individual cohort study (including low quality RCT; e.g., <80% follow-up) |
Across RCTs of different drugs v. placebo in similar or different patients with clinically important or validated surrogate outcomes |
Retrospective cohort study or follow-up of untreated control patients in an RCT; Derivation of CDR† or validated on split-sample§§§ only |
Exploratory** cohort study with good†††reference standards; CDR† after derivation, or validated only on split-sample§§§ or databases |
Retrospective cohort study, or poor follow-up |
Analysis based on clinically sensible costs or alternatives; limited review(s) of the evidence, or single studies; and including multi-way sensitivity analyses | |
|
"Outcomes" Research; Ecological studies |
"Outcomes" Research |
Ecological studies |
Audit or outcomes research | ||||
|
SR (with homogeneity*) of case-control studies |
Across subgroup analyses from RCTs of different drugs v. placebo in similar or different patients, with clinically important or validated surrogate outcome |
SR (with homogeneity*) of 3b and better studies |
SR (with homogeneity*) of 3b and better studies |
SR (with homogeneity*) of 3b and better studies | |||
|
3b |
Individual Case-Control Study |
Across RCTs of different drugs v. placebo in similar or different patients but with unvalidated surrogate outcomes |
Non-consecutive study; or without consistently applied reference standards |
Non-consecutive cohort study, or very limited population |
Analysis based on limited alternatives or costs, poor quality estimates of data, but including sensitivity analyses incorporating clinically sensible variations. | ||
| C |
Case-series (and poor quality cohort and case-control studies§§ ) |
Between non-randomised studies (observational studies and administrative database research) with clinically important outcomes |
Case-series (and poor quality prognostic studies ***) |
Case-control study, poor or non-independent reference standard |
Case-series or superseded reference standards |
Analysis with no sensitivity analysis | |
| D |
5 |
Expert opinion without explicit critical appraisal, or based on physiology, bench research or "first principles" |
Expert opinion without explicit critical appraisal, or based on physiology, bench research or "first principles"; or non-randomised studies with unvalidated surrogate outcomes |
Expert opinion without explicit critical appraisal, or based on physiology, bench research or "first principles" |
Expert opinion without explicit critical appraisal, or based on physiology, bench research or "first principles" |
Expert opinion without explicit critical appraisal, or based on physiology, bench research or "first principles" |
Expert opinion without explicit critical appraisal, or based on economic theory or "first principles" |
| * | By homogeneity we mean a systematic review that is free of worrisome variations (heterogeneity) in the directions and degrees of results between individual studies. Not all systematic reviews with statistically significant heterogeneity need be worrisome, and not all worrisome heterogeneity need be statistically significant. As noted above, studies displaying worrisome heterogeneity should be tagged with a "-" at the end of their designated level. |
| † | Clinical Decision Rule. (These are algorithms or scoring systems which lead to a prognostic estimation or a diagnostic category) |
| ‡ | See comment #2 for advice on how to understand, rate and use trials or other studies with wide confidence intervals. |
| § | Met when all patients died before the Rx became available, but some now survive on it; or when some patients died before the Rx became available, but none now die on it. |
| §§ | By poor quality cohort study we mean one that failed to clearly define comparison groups and/or failed to measure exposures and outcomes in the same (preferably blinded), objective way in both exposed and non-exposed individuals and/or failed to identify or appropriately control known confounders and/or failed to carry out a sufficiently long and complete follow-up of patients. By poor quality case-control study we mean one that failed to clearly define comparison groups and/or failed to measure exposures and outcomes in the same (preferably blinded), objective way in both cases and controls and/or failed to identify or appropriately control known confounders. |
| §§§ | Split-sample validation is achieved by collecting all the information in a single tranche, then artificially dividing this into "derivation" and "validation" samples. |
| †† | An "Absolute SpPin" is a diagnotic finding whose Specificity is so high that a Positive result rules-in the diagnosis. An "Absolute SnNout" is a diagnostic finding whose Sensitivity is so high that a Negative result rules-out the diagnosis. |
| ‡‡ | Better-value treatments are clearly as good but cheaper, or better at the same or reduced cost. Worse-value treatments are as good and more expensive, or worse and equally or more expensive. |
| ††† | Good reference standards are independent of the test, and applied blindly or objectively to applied to all patients. Poor reference standards are haphazardly applied, but still independent of the test. Use of a non-independent reference standard (where the 'test' is included in the 'reference', or where the 'testing' affects the 'reference') implies a level 4 study. |
| ** | Validating studies test the quality of a specific diagnostic test, based on prior evidence. An exploratory study collects information and trawls the data (e.g. using a regression analysis) to find which factors are 'significant'. |
| *** | By poor quality prognostic cohort study we mean one in which sampling was biased in favour of patients who already had the target outcome, or the measurement of outcomes was accomplished in <80% of study patients, or outcomes were determined in an unblinded, non-objective way, or there was no correction for confounding factors. |
| **** | Good follow-up in a differential diagnosis study is >80%, with adequate time for alternative diagnoses to emerge (eg 1-6 months acute, 1 - 5 years chronic) |
| ‡‡‡ | Surrogate outcomes are considered validated only when the relationship between the surrogate outcome and the clinically important outcomes has been established in long-term RCTs. |