Abstract
BackgroundWhile the clinical trials and statistical methodology literature on sample size re-estimation (SSRE) is robust, evaluation of SSRE procedures following the completion of a clinical trial has been sparsely reported. In blinded sample size re-estimation, only nuisance parameters are re-estimated, and the blinding of the current trial treatment effect is preserved. Blinded re-estimation procedures are well-accepted by regulatory agencies and funders. We review our experience of sample size re-estimation in a large international, National Institutes of Health funded clinical trial for adjuvant breast cancer treatment, and evaluate our blinded sample size re-estimation procedure for this time-to-event trial. We evaluated the SSRE procedure by examining assumptions made during the re-estimation process, estimates resulting from re-estimation, and the impact on final trial results with and without the addition of participants, following sample size re-estimation.MethodsWe compared the control group failure probabilities estimated at the time of SSRE to estimates used in the original planning, to the final un-blinded control group failure probability estimates for those included in the SSRE procedure (SSRE cohort), and to the final total control group failure probability estimates. The impact of re-estimation on the final comparison between randomized treatment groups is evaluated for those in the originally planned cohort (n = 340) and for the combination of those recruited in the originally planned cohort and those added after re-estimation (n = 509).ResultsVery little difference is observed between the originally planned cohort and all randomized patients in the control group failure probabilities over time or in the overall hazard ratio estimating treatment effect (originally planned cohort HR 1.25 (0.86, 1.79); all randomized cohort HR 1.24 95% CI (0.91, 1.68)). At the time of blinded SSRE, the estimated control group failure probabilities at 3 years (0.24) and 5 years (0.40) were similar to those for the SSRE cohort once un-blinded (3 years, 0.22 (0.16, 0.30); 5 years, 0.33 (0.26, 0.41)).ConclusionsWe found that our re-estimation procedure performed reasonably well in estimating the control group failure probabilities at the time of re-estimation. Particularly for time-to-event outcomes, pre-planned blinded SSRE procedures may be the best option to aid in maintaining power.Trial registrationClinicalTrials.gov, NCT00201851. Registered on 9 September 2005. Retrospectively registered.
Highlights
While the clinical trials and statistical methodology literature on sample size re-estimation (SSRE) is robust, evaluation of SSRE procedures following the completion of a clinical trial has been sparsely reported
Since our SSRE procedure was blinded, in the current work we aimed to examine assumptions made during the re-estimation process, the estimates made in the re-estimation procedure, and the impact on final trial results with and without the addition of participants
Very little difference was observed in the failure function over time or in the overall hazard ratio (HR) estimating
Summary
While the clinical trials and statistical methodology literature on sample size re-estimation (SSRE) is robust, evaluation of SSRE procedures following the completion of a clinical trial has been sparsely reported. Evaluation of sample size re-estimation procedures, following the completion of a clinical trial, has been sparsely reported in the literature [1, 2]. In blinded sample size re-estimation, only nuisance parameters are re-estimated, and the blinding of the current trial treatment effect is preserved. These nuisance parameters may include the standard deviation in the continuous outcome setting, or the control group failure probabilities in the survival (time to event) context. This class of re-estimation procedures has shown no evidence of inflating type one error and clearly maintains study integrity [13, 14]
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