Meta-analysis of noninferiority and equivalence trials: ignoring trial design leads to differing and possibly misleading conclusions

OBJECTIVE: The objective of the study is to examine the analytic approach of meta-analyses that include noninferiority or equivalence (NI/EQ) trials. STUDY DESIGN AND SETTING: We used Scopus to identify meta-analyses including NI/EQ trials. We extracted data from the meta-analyses and their included randomized clinical trials (RCTs). We used the RCT's NI/EQ margins to reinterpret the results of the meta-analyses, assessed for risk of biases unique to NI/EQ trials, and evaluated the consistency of the meta-analysis interpretation when using NI/EQ margins. RESULTS: We identified 38 unique meta-analyses including 515 RCTs, of which 125 (24.3%) were NI/EQ trials. Fourteen meta-analyses (36.8%) reported the study design of their included trials, but only one (2.6%) interpreted their pooled estimates using NI/EQ margins and none assessed for risks of bias unique to NI/EQ trials. Nearly all NI/EQ trials (n = 116, 92.8%) included in the meta-analyses reported NI/EQ margins. The meta-analyses of 30 outcomes were reinterpreted using the NI/EQ margins; reinterpretations conflicted with the conclusion of the meta-analyses in most cases (n = 20, 66.7%). CONCLUSION: Most meta-analyses including NI/EQ trials ignore trial design and do not assess risks of bias unique to NI/EQ studies. Meta-analyses addressing questions previously explored as NI/EQ should conduct an NI/EQ meta-analysis or use clear language when performing standard (i.e., superiority) meta-analyses.