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Study criteria Level of evidence Criteria for grading of recommendation Grade of recommendation Systematic review (with homogeneity) of randomised, controlled trials 1a Consistent level 1 studies A Individual, randomised, controlled trials with statistically significant results 1b All or none, i.e. prior to availability of new therapy, all died, now with therapy some survive; or, prior to therapy some died, now with therapy none die 1c Systematic review (with homogeneity) of cohort studies 2a Consistent level 2 or 3 studies (or extrapolations* from level 1 studies) B Individual cohort study (including low quality randomised controlled trial, e.g. <80% follow up) 2b Outcomes research 2c Systematic review (with homogeneity) of case-controlled studies 3a Individual case-controlled study 3b Case-series, and poor quality cohort and case-controlled studies 4 Level 4 studies (or extrapolations* from level 2 or 3 studies) C Expert opinion without explicit critical appraisal, or based on physiology, bench research or first principles 5 Level 5 evidence (or troublingly inconsistent or inconclusive studies of any level) D

*Extrapolations are where data are used in a situation that has potentially clinically important differences to the original study situation. In the case of PROSPECT, extrapolation largely refers to transferable evidence.