Interim analyses are a common feature of clinical trial design, especially for large trials in high mortality conditions such as cancer or cardiovascular disease in which the primary endpoint is often the survival time from randomization to death. A plan for a series of interim analyses in which the criteria for stopping are specified in advance is known as a sequential design, and can be constructed to prevent patients from being randomized to an evidently inferior treatment and avoid continuation of a trial that is obviously futile.
In this paper, methods for predicting the final sample size and total duration of a sequential survival study are described, and the play-off between speed of recruitment and length of follow-up is examined. The use of interim analyses to review the event rate, recruitment period, and model assumptions is discussed and software for the implementation of the methods is described. The approach is illustrated in the context of a trial seeking to establish noninferiority.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Jones DR, Whitehead J. Sequential forms of the log rank and modified Wilcoxon tests for censored data. Biometrika. 1979;66:105–113. Correction. Biometrika. 1981;68:576.
Sellke T, Siegmund D. Sequential analysis of the proportional hazards model. Biometrika. 1983;70:315–326.
Tsiatis AA, Rosner GL, Tritchler DL. Group sequential tests with censored survival data adjusting for covariates. Biometrika. 1985;72:365–373.
Moss AJ, Hall WJ, Cannom DS, Daubert JP, Higgins SL, Klein H, Levine JH, Saksena S, Waldo A, Wilber D, Brown MW, Heo M. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrythmia. New Engl J Med. 1996;335:1933–1940.
Boden WE, van Gilst WH, Scheldewaert RG, Starkey IR, Carlier MF, Julian DG, Whitehead A, Bertrand ME, Col JJ, Lederballe Pedersen O, Lie KI, Santoni J-P, Fox K. Diltiazem in acute myocardial infarction treated with thrombolytic agents: a randomised placebo-controlled trial. Lancet. 2000;355:1751–1756.
Arriagada R, Le Chevalier T, Pignon J-P, Rivière A, Monnet I, Chomy P, Tuchais C, Tarayre M, Rufflé P. Initial chemotherapeutic doses and survival in patients with limited small-cell lung cancer. New Engl J Med. 1993;329:1848–1852.
Medical Research Council Renal Cancer Collaborators. Interferon-α and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Lancet. 1999;353:14–17.
Whitehead J. Monotherapy trials: Sequential design. Epilepsy Res. 2001;43:81–87.
MPS Research Unit. PEST 4: Operating Manual. Reading, UK: The University of Reading; 2000.
Collett D. Modelling Survival Data in Medical Research. London: Chapman and Hall; 1994.
Whitehead J. The Design and Analysis of Sequential Clinical Trials. Revised second ed. Chichester, England: Wiley; 1997.
Sooriyarachchi MR, Whitehead J. The sequential analysis of survival data with non-proportional hazards. Biometrics. 1998;54:1072–1084.
Freedman LS. Tables of the numbers of patients required in clinical trials using the logrank test. Stat Med. 1982;1:121–129.
Machin D, Campbell MJ, Fayers PM, Pinol APY. Sample Size Tables for Clinical Studies. Second edition. Oxford: Blackwell Science Ltd.; 1997.
Schoenfeld DA. Sample-size formula for the proportional-hazards regression model. Biometrics. 1983;39:499–503.
Whitehead J, Whitehead A, Todd S, Bolland K, Sooriyarachchi MR. Mid-trial design reviews for sequential clinical trials. Stat Med. 2001;20:165–176.
Wittes J, Brittain E. The role of internal pilot studies in increasing the efficiency of clinical trials. Stat Med. 1990;9:65–72.
Gould AL. Interim analyses for monitoring clinical trials that do not materially effect the type I error rate. Stat Med. 1992;11:55–66.
Gould AL. Planning and revising the sample size for a trial. Stat Med. 1995;14:1039–1051.
Gould AL, Shih WJ. Sample size re-estimation without unblinding for normally distributed data with unknown variance. Comm Stat—Theory Methods. 1992;21:2833–2853.
Whitehead. Sequential designs for equivalence studies. Stat Med. 1996;15:2703–2715.
Whitehead J. Overrunning and underrunning in sequential clinical trials. Control Clin Trials. 1992;13:106–121.
Gould AL, Shih WJ. Modifying the design of ongoing trials without unblinding. Stat Med. 1998;17:89–100.
Stallard N, Facey KM. Comparison of the spending function method and the Christmas tree correction for group sequential trials. J Biopharmaceutical Stat. 1996;6:361–373.
Fairbanks K, Madsen R. P values for tests using a repeated significance test design. Biometrika. 1982;69:69–74.
Cytel Software Corporation. EaSt 2000: A Software Package for the Design and Interim Monitoring of Group Sequential Clinical Trials. Cambridge MA: Cytel; 2000.
Gregory WM, Bolland KM, Whitehead J, Souhami RL. Cautionary tales of survival analysis: conflicting analyses from a clinical trial in breast cancer. Br J Cancer. 1997;76:551–558.
George SL, Desu MM. Planning the size and duration of a clinical trial studying the time to some critical event. J Chronic Dis. 1974;27:15–24.
Schoenfeld DA, Richter JR. Nomograms for calculating the number of patients needed for a clinical trial with survival as an endpoint. Biometrics. 1982;38:163–170.
About this article
Cite this article
Whitehead, J. Predicting the Duration of Sequential Survival Studies. Ther Innov Regul Sci 35, 1387–1400 (2001). https://doi.org/10.1177/009286150103500435
- Interim analysis
- Sequential analysis
- Survival analysis