RECOMMENDATIONS FOR PRACTICE
SECONDARY, APPENDIX
Stratification errors can occur in any trial that uses stratified randomisation. We encourage researchers to consider the possibility of stratification errors at all stages of the trial and provide 10 general recommendations for addressing these errors during the design, conduct, analysis and reporting of the trial in Table Recommendations for addressing stratification errors by trial stage in trials using stratified randomisation.Implement strategies to minimise the risk of stratification errors, such as clearly defining stratification variables, avoiding stratification variables that are likely to be subject to high levels of misclassification, training staff to carefully check the stratification variables before randomising participants, and designing randomisation systems that are easy to use.Pre‐specify how stratification errors will be addressed in the primary analysis and any planned secondary or subgroup analyses in the statistical analysis plan.If the discovery of errors is unlikely to be related to treatment group (eg, in a blinded trial), then (i) adjust for the updated strataIf the discovery of errors could plausibly be related to treatment group (eg, in an unblinded trial involving more contact with intervention participants), then (i) adjust for the randomisation strataImplement systematic strategies to identify stratification errors across all participants, such as cross‐checking stratification variables against alternate data sources (where available).Thoroughly document any stratification errors that are identified, including how they occurred, to assist with staff training and inform the design of future trials.Record the updated strataExamine the number of stratification errors that were identified overall and broken down by treatment group, stratum and their combination.Address stratification errors in the planned analyses using the approach(es) pre‐specified in the statistical analysis plan.Consider whether any additional, unplanned analyses should be performed, based on the number and pattern of stratification errors that were identified in the trial (eg, a sensitivity analysis excluding participants affected by stratification errors).Report the number of stratification errors that were identified by treatment group and stratum, potentially in a Supplementary Appendix S1, or state that no such errors were identified.Indicate whether the randomisation strataThe In most trials, the discovery of stratification errors is unlikely to be related to treatment group. For example, in blinded trials the research staff typically have similar amounts of contact with participants in each group, providing similar opportunities for errors to be discovered in each group. In this case, we recommend adjusting for the updated strata in the primary analysis for all trial outcomes (Recommendation 2a) due to its power advantages. Adjusting for the randomisation strata should be considered in a sensitivity analysis, at least for the primary outcome, to explore the impact of any stratification errors on the trial results. If subgroup analyses by the stratification variable are planned, we recommend using the updated strata to define the subgroups and perform the interaction test in order to minimise any bias in the subgroup effect estimates.An exception to these recommendations should be made when the discovery of stratification errors could plausibly be related to treatment group. This can occur, for example, in unblinded trials involving substantially greater contact with trial participants assigned to one treatment arm and hence providing a greater opportunity for stratification errors to be discovered among these participants. In this setting, we recommend adjusting for the randomisation strata in the primary analysis for all trial outcomes (Recommendation 2b) to avoid the risk of introducing bias into the treatment effect estimates. Adjusting for the updated strata should be performed in a sensitivity analysis, at least for the primary outcome, to explore the impact of any stratification errors on the trial results, while acknowledging the results of this sensitivity analysis could be biased. The risk of bias can be judged by examining and reporting the number of stratification errors that were identified by treatment group, with bias expected when the discovery of stratification errors is more common in one group. If subgroup analyses by the stratification variable are planned, we recommend using the randomisation strata to define the subgroups and perform the interaction test. Although this approach will likely be biased and this should be acknowledged, less bias is expected compared to using the updated strata in this setting.Existing analysis guidelines state that ‘if one or more factors are used to stratify the design, it is appropriate to account for those factors in the analysis’