GRADEing the quality of evidence on safety: an adapted GRADE approach for preparing lists of potentially inappropriate medication for older adults

Background: Systematic reviews that synthesize safety outcomes pose challenges (e.g. rare events), which poses questions for grading the strength of the body of evidence. In this contribution, we suggest adaption of the GRADE system for grading the quality of evidence on safety outcomes for developing a potentially inappropriate medication list (PRISCUS). Methods: We systematically assessed each of the five GRADE domains for rating-down (study limitations, imprecision, inconsistency, indirectness, publication bias) and the criteria for rating-up, considering if special considerations or revisions of the original approach were indicated. The result was gathered in a written document and discussed in a group-meeting. Subsequently, we performed a proof-of-concept application using a convenience sample of systematic reviews. Results: We adapted aspects of the criteria study limitations, imprecision, publication bias and rating-up for large effect. In addition, we suggest a new criterion to account for data from subgroup-analyses. The proof-of-concept application did not reveal a need for further revision and thus we used the approach for the systematic reviews that were prepared for the PRISCUS-list. We assessed 51 outcomes for 19 clinical questions. Each of the proposed adaptions was applied. There were neither an excessive number of low and very low ratings, nor an excessive number of high ratings, but the different methodological quality of the safety outcomes appeared to be well reflected. Conclusion: The adaptions appear to have the potential to overcome some of the challenges when grading the methodological quality of harms and thus may be helpful for producers of evidence syntheses considering safety.