Flexible sequential designs for multi‐arm clinical trials

Adaptive designs that are based on group-sequential approaches have the benefit of being efficient as stopping boundaries can be found that lead to good operating characteristics with test decisions based solely on sufficient statistics. The drawback of these so called 'pre-planned adaptive' designs is that unexpected design changes are not possible without impacting the error rates. 'Flexible adaptive designs' on the other hand can cope with a large number of contingencies at the cost of reduced efficiency. In this work, we focus on two different approaches for multi-arm multi-stage trials, which are based on group-sequential ideas, and discuss how these 'pre-planned adaptive designs' can be modified to allow for flexibility. We then show how the added flexibility can be used for treatment selection and sample size reassessment and evaluate the impact on the error rates in a simulation study. The results show that an impressive overall procedure can be found by combining a well chosen pre-planned design with an application of the conditional error principle to allow flexible treatment selection.

[1]  Tim Friede,et al.  A Comparison of Methods for Adaptive Treatment Selection , 2008, Biometrical journal. Biometrische Zeitschrift.

[2]  G. Hommel.  Adaptive Modifications of Hypotheses After an Interim Analysis , 2001 .

[3]  Richard Simon,et al.  Two-stage selection and testing designs for comparative clinical trials , 1988 .

[4]  Tim Friede,et al.  A group‐sequential design for clinical trials with treatment selection , 2008, Statistics in medicine.

[5]  M Kieser,et al.  Combining different phases in the development of medical treatments within a single trial. , 1999, Statistics in medicine.

[6]  Martin Posch,et al.  Testing and estimation in flexible group sequential designs with adaptive treatment selection , 2005, Statistics in medicine.

[7]  D A Follmann,et al.  Monitoring pairwise comparisons in multi-armed clinical trials. , 1994, Biometrics.

[8]  S. Holm.  A Simple Sequentially Rejective Multiple Test Procedure , 1979 .

[9]  C. Burman,et al.  Are Flexible Designs Sound? , 2006, Biometrics.

[10]  W. Brannath,et al.  Recursive Combination Tests , 2002 .

[11]  F. Bretz,et al.  Compatible simultaneous lower confidence bounds for the Holm procedure and other Bonferroni‐based closed tests , 2008, Statistics in medicine.

[12]  Nigel Stallard,et al.  A confirmatory seamless phase II/III clinical trial design incorporating short‐term endpoint information , 2010, Statistics in medicine.

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

[14]  T. W. Anderson,et al.  An Introduction to Multivariate Statistical Analysis , 1959 .

[15]  T. Hothorn,et al.  Multivariate Normal and t Distributions , 2016 .

[16]  L Di Scala,et al.  Time‐to‐event analysis with treatment arm selection at interim , 2011, Statistics in medicine.

[17]  B. Turnbull,et al.  Group Sequential Methods with Applications to Clinical Trials , 1999 .

[18]  M. Proschan,et al.  Designed extension of studies based on conditional power. , 1995 .

[19]  Werner Brannath,et al.  Multiplicity and flexibility in clinical trials , 2007, Pharmaceutical statistics.

[20]  H. Schäfer,et al.  A general statistical principle for changing a design any time during the course of a trial , 2004, Statistics in medicine.

[21]  John Whitehead,et al.  One‐ and two‐stage design proposals for a phase II trial comparing three active treatments with control using an ordered categorical endpoint , 2009, Statistics in medicine.

[22]  C. Jennison,et al.  An adaptive seamless phase II/III design for oncology trials with subpopulation selection using correlated survival endpoints † , 2011, Pharmaceutical statistics.

[23]  A. Tsiatis,et al.  On the inefficiency of the adaptive design for monitoring clinical trials , 2003 .

[24]  K. Gabriel,et al.  On closed testing procedures with special reference to ordered analysis of variance , 1976 .

[25]  Eric V. Slud,et al.  Two-Sample Repeated Significance Tests Based on the Modified Wilcoxon Statistic , 1982 .

[26]  Christopher Jennison,et al.  Adaptive and nonadaptive group sequential tests , 2006 .

[27]  W. Lehmacher,et al.  Adaptive Sample Size Calculations in Group Sequential Trials , 1999, Biometrics.

[28]  Bruce W Turnbull,et al.  Confirmatory Seamless Phase II/III Clinical Trials with Hypotheses Selection at Interim: Opportunities and Limitations , 2006, Biometrical journal. Biometrische Zeitschrift.

[29]  Thomas J. Santner,et al.  Design of Experiments: Ranking and Selection , 1984 .

[30]  P. Bauer,et al.  Modification of the sample size and the schedule of interim analyses in survival trials based on data inspections by H. Schäfer and H.‐H. Müller, Statistics in Medicine 2001; 20: 3741–3751 , 2004, Statistics in medicine.

[31]  Helmut Schäfer,et al.  Interim Design Modifications in Time-to-Event Studies , 2012 .

[32]  Anja Vogler,et al.  An Introduction to Multivariate Statistical Analysis , 2004 .

[33]  Nigel Stallard,et al.  Sequential designs for phase III clinical trials incorporating treatment selection , 2003, Statistics in medicine.

[34]  C. Dunnett.  A Multiple Comparison Procedure for Comparing Several Treatments with a Control , 1955 .

[35]  P. Bauer,et al.  Evaluation of experiments with adaptive interim analyses. , 1994, Biometrics.

[36]  D. DeMets,et al.  Some drop‐the‐loser designs for monitoring multiple doses , 2010, Statistics in medicine.

[37]  John Weiner,et al.  Letter to the Editor , 1992, SIGIR Forum.

[38]  Nigel Stallard,et al.  An Adaptive Group Sequential Design for Phase II/III Clinical Trials that Select a Single Treatment From Several , 2005, Journal of biopharmaceutical statistics.

[39]  J. Whitehead,et al.  A generalized Dunnett Test for Multi-arm Multi-stage Clinical Studies with Treatment Selection , 2012 .

[40]  Anthony J. Hayter,et al.  On the Relationship between Stepwise Decision Procedures and Confidence Sets , 1994 .

[41]  T. Friede,et al.  A conditional error function approach for subgroup selection in adaptive clinical trials , 2012, Statistics in medicine.

[42]  Frank Bretz,et al.  Adaptive Dunnett tests for treatment selection , 2008, Statistics in medicine.

[43]  D Magirr,et al.  Simultaneous confidence intervals that are compatible with closed testing in adaptive designs , 2013, Biometrika.