Box 17.

Exemplars on reporting item 12 elements

Example 1. GSD; statistical method for estimating treatment effects “Stagewise ordering was used to compute the unbiased median estimate and confidence limits for the prognosis-group-adjusted hazard rates [250]. ” [251] Example 2. Inferentially seamless (4-arm 2-stage) AD with dose selection; statistical methods for controlling operating characteristics “…the power of the study ranged from 71 to > 91% to detect a treatment difference at a one-sided α of 0.025 when the underlying response rate of ≥1 of the crofelemer dose groups exceeded placebo by 20%. The clinical response of 20% was based on an estimated response rate of 55% in crofelemer and 35% in placebo during the 4-week placebo-controlled assessment period.… For the primary endpoint, the test for comparing the placebo and treatment arms reflected the fact that data were gathered in an adaptive fashion and controlled for the possibility of an increased Type I error rate. Using the methods of Posch and Bauer [64], as agreed upon during the special protocol assessment process, a p-value was obtained for comparison of each dose to the placebo arm from the stage I data, and an additional p-value was obtained for comparison of the optimal dose to the placebo arm from the independent data gathered in stage II. For the final primary analysis, the p-values from the first and second stages were combined by the inverse normal weighting combination function, and a closed testing procedure was implemented to test the null hypothesis using the methods of Posch and Bauer [64], based on the original work of Bauer and Kieser [65]. This closed test controlled the experiment-wise error rate for this 2-stage adaptive design at a one-sided α of 0.025.” [252] Extracted from appendix material. Example 3. 3-arm 2-stage group-sequential AD with treatment selection; combination test method; multiplicity adjustments; statistical method for estimating treatment effects “The proposed closed testing procedure will combine weighted inverse normal combination tests using pre-defined fixed weights, the closed testing principle [64, 253, 254], and the Hochberg-adjusted 1-sided P-value on stage 1 data. This testing procedure strongly controls the overall type I error rate at α level (see “Simulations run to assess the type I error rate under several null hypothesis scenarios”). Multiplicity-adjusted flexible repeated 95% 2-sided CIs [217] on the percentage of patients will be calculated for otamixaban dose 1, otamixaban dose 2, and UFH plus eptifibatide. Relative risk and its 95% 2-sided CIs will also be calculated. Point estimates based on the multiplicity-adjusted flexible repeated CIs will be used.” [181] See supplementary material of the paper for details. Example 4. Population-enrichment AD with SSR; criteria for claiming evidence of benefit; methods for controlling familywise type I error; combination test weights Mehta et al. [95] published a methodological paper detailing a family of three hypotheses being tested; use of closure testing principle [254] to control the overall type I error; how evidence is claimed; and analytical derivations of the Simes adjusted p-values [255]. This includes the use of a combination test approach using pre-defined weights based on the accrued information fraction for the full population (cutaneous and non-cutaneous patients) and subpopulation (cutaneous patients). Analytical derivations were presented for the two cases assuming enrichment occurs at interim analysis and no enrichment after interim analysis. Details are reported in a supplementary file accessible via the journal website. Example 5. Inferentially seamless (7-arm 2-stage) AD with dose selection; use of traditional naïve estimates “Unless otherwise stated, efficacy data are given as least squares means with standard error (SE) or 95% confidence interval (CI).” [76] Example 6. Inferentially seamless phase 2/3 (5-arm 2-stage) AD with dose selection; dealing with overrunning participants “Patients already assigned to an unselected regimen of propranolol by the time that the conclusions of the interim analysis are available, will continue the treatment according to the protocol but efficacy data for these patients will not be included in the primary analysis of primary endpoint.” [94] Extracted from the supplementary material.