title: Variance estimation in clinical studies with interim sample size re-estimation.
abstract: We consider clinical studies with a sample size re-estimation based on the unblinded variance estimation at some interim point of the study. Because the sample size is determined in such a flexible way, the usual variance estimator at the end of the trial is biased. We derive sharp bounds for this bias. These bounds have a quite simple form and can help for the decision if this bias is negligible for the actual study or if a correction should be done. An exact formula for the bias is also provided. We discuss possibilities to get rid of this bias or at least to reduce the bias substantially. For this purpose, we propose a certain additive correction of the bias. We see in an example that the significance level of the test can be controlled when this additive correction is used.
authors: Clinical Information Science Department, AstraZeneca, S-15185 Södertälje, Sweden. frank.miller@astrazeneca.com
authors: Frank
authors: F
authors: Miller
mesh_terms: D000704:Analysis of Variance; D015982:Bias; D035843:Biomedical Research / Q000379:methods; D001699:Biometry / Q000379:methods*; D002986:Clinical Trials as Topic / Q000379:methods*; D003627:Data Interpretation, Statistical; D004311:Double-Blind Method; D006801:Humans; D015233:Models, Statistical; D008962:Models, Theoretical; D010865:Pilot Projects; D012107:Research Design; D018401:Sample Size; D013997:Time Factors; D016896:Treatment Outcome