Subgroup analysis in haematologic malignancies phase III clinical trials: A systematic review

Aims To assess the appropriateness of the use and interpretation of subgroup analysis in haematology randomized clinical trials (RCTs). Method A systematic review of Medline, including haematology phase III RCTs published between January 2013 and October 2019, was carried out to identify reported subgroup analysis. Information related to trial characteristics, subgroup analysis and claims of subgroup difference were collected. Results The initial search identified 1622 studies. A total of 98 studies reporting subgroup analyses were identified. Of those, 24 RCT reported 46 claims of subgroup difference. Among them, 44 were claims for the primary outcome, of which 25 were considered strong claims and 17 were considered suggestions of a possible effect. Authors included subgroup variables for the primary outcome measured at baseline for 38 claims (n = 86.36%), used a subgroup variable as a stratification factor at randomization for 15 (34.09%), clearly prespecified their hypothesis for 11 (25%), the subgroup effect was one of a small number of hypothesised effects tested (<= 5) for 17 (38.64%), carried out a test of interaction that provide statistically significant for 18 (40.91%), documented replication of a subgroup effect with previously related studies for 11 (25%), identified the consistency of a subgroup effect across related outcome for 10 (22.72%) and provided a biological rationale for the effect for 8 (18.18%). Of the 44 claims for the primary outcome, 34 (77.27%) met four or fewer of the 10 credibility criteria. Conclusion The subgroup claims reported in haematology RCTs lack credibility, even when the claims are strong. Information about subgroup difference should be interpreted cautiously.