title: Interim analysis for binary outcome trials with a long fixed follow-up time and repeated outcome assessments at pre-specified times.
abstract: In trials with binary outcomes, assessed repeatedly at pre-specified times and where the subject is considered to have experienced a failure at the first occurrence of the outcome, interim analyses are performed, generally, after half or more of the subjects have completed follow-up. Depending on the duration of accrual relative to the length of follow-up, this may be inefficient, since there is a possibility that the trial will have completed accrual prior to the interim analysis. An alternative is to plan the interim analysis after subjects have completed follow-up to a time that is less than the fixed full follow-up duration. Using simulations, we evaluated three methods to estimate the event proportion for the interim analysis in terms of type I and II errors and the probability of early stopping. We considered: 1) estimation of the event proportion based on subjects who have been followed for a pre-specified time (less than the full follow-up duration) or who experienced the outcome; 2) estimation of the event proportion based on data from all subjects that have been randomized by the time of the interim analysis; and 3) the Kaplan-Meier approach to estimate the event proportion at the time of the interim analysis. Our results show that all methods preserve and have comparable type I and II errors in certain scenarios. In these cases, we recommend using the Kaplan-Meier method because it incorporates all the available data and has greater probability of early stopping when the treatment effect exists.
authors.affiliation: Ontario Clinical Oncology Group, Department of Oncology, McMaster University, 711 Concession Street - G (60) Wing 1st Floor, Hamilton, ON L8V 1C3 Canada.
authors.forename: Sameer
authors.initials: S
authors.lastname: Parpia
authors.affiliation: Ontario Clinical Oncology Group, Department of Oncology, McMaster University, 711 Concession Street - G (60) Wing 1st Floor, Hamilton, ON L8V 1C3 Canada.
authors.forename: Jim A
authors.initials: JA
authors.lastname: Julian
authors.affiliation: Ontario Clinical Oncology Group, Department of Oncology, McMaster University, 711 Concession Street - G (60) Wing 1st Floor, Hamilton, ON L8V 1C3 Canada.
authors.forename: Chushu
authors.initials: C
authors.lastname: Gu
authors.affiliation: Biostatistics Unit - FSORC, St Joseph's Healthcare - Hamilton, 50 Charlton Avenue East, Hamilton, ON L8N 4A6 Canada.
authors.forename: Lehana
authors.initials: L
authors.lastname: Thabane
authors.affiliation: Ontario Clinical Oncology Group, Department of Oncology, McMaster University, 711 Concession Street - G (60) Wing 1st Floor, Hamilton, ON L8V 1C3 Canada.
authors.forename: Mark N
authors.initials: MN
authors.lastname: Levine
keywords: Binary outcome; Interim analysis; Power; Type I error