Abstract
The use of alpha-spending functions has become a powerful tool in designing group sequential trials since 1990. In this manuscript, we present practical problems that we encountered and suggest possible solutions. Since group sequential methods deal with only one endpoint, they have certain intrinsic limitations in medical research. As a result, we often modify the design in conducting clinical trials since the sequential statistical framework is not sophisticated enough to handle many practical problems related to multiple endpoints in clinical trials. Topics discussed include the choice of a primary endpoint; the use of symmetric and asymmetric boundaries in interim analysis; data-driven interim analyses; overruling of a group sequential boundary; comparison of two means and the use of logrank tests in survival trials.
Similar content being viewed by others
References
Armitage P, McPherson CK, Rowe BC (1969) Repeated significance tests on accumulating data. J R Stat Soc, Ser A 132:235–244
Chen JYH, DeMets DL, Lan KKG (2003) Monitoring mortality at interim analyses while testing a composite endpoint at the final analysis. Control Clin Trials 24:16–27
Cook T, DeMets DL (2008) Introduction to statistical methods for clinical trials. Chapman & Hall/CRC, Boca Raton
DeMets DL, Ware JH (1980) Asymmetric group sequential boundaries for monitoring clinical trials. Biometrika 67:651–660
East5 Manual (2007) Cytel Inc., Cambridge, MA
Ellenberg S, Fleming T, DeMets D (2002) Data monitoring committees in clinical trials: a practical perspective. Wiley, West Sussex
Friedman LM, Furberg CD, DeMets DL (1998) Fundamentals of clinical trials, 3rd edn. Springer, New York
Hwang IK, Shih WJ, DeCani JS (1990) Group sequential designs using a family of type I error probability spending functions. Stat Med 9:1939–1445
Kim K, DeMets DL (1987) Design and analysis of group sequential tests based on the type I error spending rate function. Biometrika 74:149–154
Lan KKG, DeMets DL (1983) Discrete sequential boundaries for clinical trials. Biometrika 70(3):659–663
Lan KKG, DeMets DL (1989) Changing frequency of interim analysis in sequential monitoring. Biometrics 45:1017–1020
Lan KKG, DeMets DL (1989) Group sequential procedures: Calendar versus information time. Stat Med 8:1191–1198
Lan KKG, Lachin JM (1990) Implementation of group sequential logrank tests in a maximum duration trial. Biometrics 46:759–770
Lan KKG, Lachin JM, Bautista O (2003) Overruling of a group sequential boundary—a stopping rule versus a guideline. Stat Med 22:3347–3355
Lan KKG, Hu P, Proschan MA (2009) A conditional power approach to the evaluation of predictive power. Stat Biopharm Res 1(2):131–136. doi:10.1198/sbr.2009.0035
O’Brien PC, Fleming TR (1979) A multiple testing procedure for clinical trials. Biometrics 35:549–556
Pampallona S, Tsiatis AA, Kim K (2001) Interim monitoring of group sequential trials using spending functions for the type I and type II error probabilities. Drug Inf J 35:1113–1121
Pocock SJ (1977) Group sequential methods in the design and analysis of clinical trials. Biometrika 64:191–199
Proschan MA (1999) Properties of spending function boundaries. Biometrika 86:466–473
Proschan MA, Follmann DA, Waclawiw MA (1992) Effects of assumption violations on type I error rate in group sequential monitoring. Biometrics 48:1131–1133
Proschan MA, Lan KKG, Wittes JT (2006) Statistical monitoring of clinical trials: a unified approach. Springer, New York
Reboussin DM, DeMets DL, Kim KM, Lan KKG (1995) Programs for computing group sequential bounds using the Lan–DeMets method, Version 2.1, UW Department of Biostatistics, Technical Report No 95, October 1995
Reboussin DM, DeMets DL, Kim KM, Lan KKG (2000) Computations for group sequential boundaries using the Lan–DeMets spending function method. Control Clin Trials 21(3):190–207
Spiegelhalter DJ, Freedman LS, Blackburn PR (1986) Monitoring clinical trials: conditional or predictive power? Control Clin Trials 7:8–17
Taylor AL, Ziesche S, Yancy C, Carson P, D’Agostino R Jr, Ferdinand K, Taylor M, Adams K, Sabolinski M, Worcel M, Cohn JN (for the African–American Heart Failure Trial Investigators) (2004) Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. New Engl J Med 351(20):2049–2057
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lan, K.K.G., DeMets, D. Further Comments on the Alpha-Spending Function. Stat Biosci 1, 95–111 (2009). https://doi.org/10.1007/s12561-009-9004-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12561-009-9004-3