Table 1 overview of adaptions

Study type/methodological quality

NRS start as “low quality” of evidence^a

Data on harms from RCTs is often insufficient and thus it is advisable to consider NRS

NRS start as “high quality” of evidence if rated as low risk for confounding and selection bias

Imprecision (binary outcomes)

Usually, 95% of CIs of relative effects are used

95%CI overlaps decision threshold (e.g. null effect) → rating down one level

95%CI includes appreciable harm and benefit → rating down two levels

Harms are often rare events and rare in the included studies despite large sample sizes. In the case of rare events 95% CIs of relative effects can be misleading.

Imprecision is assessed based on absolute effects

Publication bias/missing results in the synthesis

Rating down for publication bias

For harms selective dissemination would result in underestimation of harms

Rating up for publication bias

Large magnitude of effect

Rating up if RR >2 (<0.5)

Harms are usually less affected by confounding by indication

Rating up if RR >1.67 (<0.60)

Originally not used

Subgroup effects

Harms are often subgroup-specific but analysis within subgroups is underpowered

Rating up if there is a statistically significant subgroup effect from a well-designed subgroup analysis