Background: Recommendations for statistical methods in rare disease trials are scarce, especially for cross-over designs. As a result various state-of-the-art methodologies were compared as neutrally as possible using an illustrative data set from epidermolysis bullosa research to build recommendations for count, binary, and ordinal outcome variables. For this purpose, parametric (model averaging), semiparametric (generalized estimating equations type [GEE-like]) and nonparametric (generalized pairwise comparisons [GPC] and a marginal model implemented in the R package nparLD) methods were chosen by an international consortium of statisticians.
Results: It was found that there is no uniformly best method for the aforementioned types of outcome variables, but in particular situations, there are methods that perform better than others. Especially if maximizing power is the primary goal, the prioritized unmatched GPC method was able to achieve particularly good results, besides being appropriate for prioritizing clinically relevant time points. Model averaging led to favorable results in some scenarios especially within the binary outcome setting and, like the GEE-like semiparametric method, also allows for considering period and carry-over effects properly. Inference based on the nonparametric marginal model was able to achieve high power, especially in the ordinal outcome scenario, despite small sample sizes due to separate testing of treatment periods, and is suitable when longitudinal and interaction effects have to be considered.
Conclusion: Overall, a balance has to be found between achieving high power, accounting for cross-over, period, or carry-over effects, and prioritizing clinically relevant time points.
Keywords: Cross-over; Epidermolysis bullosa simplex; GEE-like semiparametric model; Generalized pairwise comparison (GPC); Guidance; Model averaging; NparLD; Rare Diseases; Recommendation; Repeated measures; Small sample size.
© 2023. The Author(s).