Clinical trial designs based on sequential conditional probability ratio tests and reverse stochastic curtailing.

We propose a group sequential method based on the sequential conditional probability ratio test and show that it has the conservatism desired in practice. We also propose calculating the discordant probability, that is, the probability that the sequential test concludes differently from a fixed-sample test at the planned end of the trial, recognizing that this probability could be substantial, even if the sequential test has the same size and power as the fixed-sample size test at the planned end of the study. In addition, we show that the proposed method can be used as a stochastic curtailing tool. Thus, the method accommodates unplanned interim analyses as well as those deemed necessary based on data trends, virtually without inflating the type I error, but it is less conservative than the usual stochastic curtailing. The method is implemented through an interactive computer program.

[1]  Anastasios A. Tsiatis,et al.  Group sequential designs for one-sided and two-sided hypothesis testing with provision for early stopping in favor of the null hypothesis , 1994 .

[2]  K. K. Lan,et al.  Stochastically curtailed tests in long–term clinical trials , 1982 .

[3]  Christopher Jennison,et al.  Bootstrap Tests and Confidence Intervals for a Hazard Ratio When the Number of Observed Failures is Small, With Applications to Group Sequential Survival Studies , 1992 .

[4]  D L DeMets,et al.  Interim analysis: the alpha spending function approach. , 1994, Statistics in medicine.

[5]  J. Haybittle,et al.  Repeated assessment of results in clinical trials of cancer treatment. , 1971, The British journal of radiology.

[6]  David L. DeMets,et al.  Asymmetric group sequential boundaries for monitoring clinical trials , 1982 .

[7]  Christopher Jennison,et al.  An improved method for deriving optimal one-sided group sequential tests , 1992 .

[8]  R Simon,et al.  Some practical aspects of the interim monitoring of clinical trials. , 1994, Statistics in medicine.

[9]  Mitchell H. Gail,et al.  Simulation Studies on Increments of the Two-Sample Logrank Score Test for Survival Time Data, with Application to Group Sequential Boundaries , 1982 .

[10]  S. Pocock.  Group sequential methods in the design and analysis of clinical trials , 1977 .

[11]  D. Zucker,et al.  Sequential monitoring of clinical trials: the role of information and Brownian motion. , 1993, Statistics in medicine.

[12]  Xiaoping Xiong,et al.  A Class of Sequential Conditional Probability Ratio Tests , 1995 .

[13]  K. K. Lan,et al.  Discrete sequential boundaries for clinical trials , 1983 .

[14]  R. Souhami,et al.  The clinical importance of early stopping of randomized trials in cancer treatments. , 1994, Statistics in medicine.

[15]  Anastasios A. Tsiatis,et al.  Repeated Significance Testing for a General Class of Statistics Used in Censored Survival Analysis , 1982 .

[16]  David L. DeMets,et al.  Statistical aspects of early termination in the beta-blocker heart attack trial , 1984 .

[17]  S. Pocock,et al.  When to stop a clinical trial. , 1992, BMJ.

[18]  E. Lehmann.  Testing Statistical Hypotheses , 1960 .

[19]  David L. DeMets,et al.  Group sequential methods for clinical trials with a one-sided hypothesis , 1980 .

[20]  Christopher Jennison,et al.  Statistical Approaches to Interim Monitoring of Medical Trials: A Review and Commentary , 1990 .

[21]  David M. Reboussin,et al.  Information and information fractions for design and sequential monitoring of clinical trials , 1994 .

[22]  R Sylvester,et al.  A reversal of fortune: practical problems in the monitoring and interpretation of an EORTC breast cancer trial. , 1994, Statistics in medicine.

[23]  Christopher Jennison,et al.  Efficient group sequential tests with unpredictable group sizes , 1987 .

[24]  J. Whitehead,et al.  A FORTRAN program for the design and analysis of sequential clinical trials. , 1983, Computers and biomedical research, an international journal.

[25]  X. Xiong,et al.  Continuous and group sequential conditional probability ratio tests for phase II clinical trials. , 1996, Statistics in medicine.

[26]  T R Fleming,et al.  Symmetric group sequential test designs. , 1989, Biometrics.

[27]  P. Armitage,et al.  Design and analysis of randomized clinical trials requiring prolonged observation of each patient. I. Introduction and design. , 1976, British Journal of Cancer.

[28]  D L Demets,et al.  Group sequential procedures: calendar versus information time. , 1989, Statistics in medicine.

[29]  J Whitehead,et al.  Sequential methods based on the boundaries approach for the clinical comparison of survival times. , 1994, Statistics in medicine.

[30]  P. O'Brien,et al.  A multiple testing procedure for clinical trials. , 1979, Biometrics.

[31]  M H Gail,et al.  Use of logrank tests and group sequential methods at fixed calendar times. , 1985, Biometrics.