Seamless phase II/III designs
Abstract
In recent years, there has been a drive to save development costs and shorten time-to-market of new therapies. Research into novel trial designs to facilitate this goal has led to, amongst other approaches, the development of methodology for seamless phase II/III designs. Such designs allow treatment or dose selection at an interim analysis and comparative evaluation of efficacy with control, in the same study. Methods have gained much attention because of their potential advantages compared to conventional drug development programmes with separate trials for individual phases. In this article, we review the various approaches to seamless phase II/III designs based upon the group-sequential approach, the combination test approach and the adaptive Dunnett method. The objective of this article is to describe the approaches in a unified framework and highlight their similarities and differences to allow choice of an appropriate methodology by a trialist considering conducting such a trial.
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References
Sheiner LB. Learning versus confirming in clinical drug development. Clinical Pharmacology and Therapeutics 1997; 61: 275–91.
Bretz F, Schmidli S, König F, Racine A, Maurer W. Confirmatory seamless phase II/III clinical trials with hypotheses selection at interim: general concepts. Biometrical Journal 2006; 48: 623–34.
Schmidli H, Bretx F, Racine A, Maurer W. Confirmatory seamless phase II/III clinical trials with hypotheses selection at interim: applications and practical considerations. Biometrical Journal 2006; 48: 635–43.
Gallo P, Chuang-Stein C, Dragalin V, Gaydos B, Krams M, Pinheiro J. Adaptive designs in clinical drug development: an executive summary of the PhRMA Working Group. Journal of Biopharmaceutical Statistics 2006; 16: 275–83.
Maca J, Bhattacharya S, Dragalin V, Gallo P, Krams M. Adaptive seamless Phase II/III designs : background, operational aspects, and examples. Drug Information Journal 2006; 40: 463–73.
Stallard N, Todd S. Sequential designs for phase III clinical trials incorporating treatment selection. Statistics in Medicine 2003; 22: 689–703.
Bauer P, Kieser M. Combining different phases in the development of medical treatments within a single trial. Statistics in Medicine 1999; 18: 1833–48.
Koenig F, Brannath W, Bretz F, Posch M. Adaptive Dunnett tests for treatment selection. Statistics in Medicine 2008; 27: 1612–25.
Jennison C, Turnbull BW. Group-sequential analysis incorporating covariate information. Journal of the American Statistical Association 1987; 92: 1330–41.
Hochberg Y, Tamhane A. Multiple comparison methods. Statistics in Medicine 2001; 20: 3861–73.
Marcus R, Peritz E, Gabriel KR. On closed testing procedures with special reference to ordered analysis of variance. Biometrika 1976; 63: 655–60.
Dunnett CW. A multiple comparison procedure for comparing several treatments with a control. Journal of the American Statistical Association 1955; 50: 1096–121.
Kelly PJ, Sooriyarachchi MR, Stallard N, Todd S. A practical comparison of group-sequential and adaptive designs. Journal of Biopharmaceutical Statistics 2005; 15: 719–38.
Müller H-H, Schäfer H. Adaptive group sequential designs for clinical trials: combining the advantages of the adaptive and of classical group sequential approaches. Biometrics 2001; 57: 886–91.
Whitehead J. The design and analysis of sequential clinical trials 1997; Chichester: Wiley.
Jennison C, Turnbull BW. Group sequential methods with applications to clinical trials 2000; London: Chapman & Hall.
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 1983; 70: 659–63.
Kim K, DeMets DL. Design and analysis of group sequential tests based on the type I error spending rate function. Biometrika 1987; 74: 149–54.
Stallard N, Facey KM. Comparison of the spending function method and the Christmas tree correction for group sequential trials. Journal of Biopharmaceutical Statistics 1990; 6: 361–73.
Armitage P, McPherson CK, Rowe BC. Repeated significance tests on accumulating data. Journal of the Royal Statistical Society, Series A 1969; 132: 235–44.
Jennison C. Tartar ME, Lock MD. Numerical computations for group sequential tests. Computing Science and Statistics: Proceedings of the 25th Symposium on the Interface 1993; California: Interface Foundation of America, 253–72.
Bauer P, Köhne K. Evaluation of experiments with adaptive interim analyses. Biometrics 1994; 51: 1315–24.
Lehmacher W, Wassmer G. Adaptive sample size calculations in group sequential tests. Biometrics 1999; 55: 1286–90.
Brannath W, Posch M, Bauer P. Recursive Combination Tests. Journal of the American Statistical Association 2002; 97: 236–44.
Müller H-H, Schäfer H. A general statistical principle for changing a design any time during the course of a trial. Statistics in Medicine 2004; 23: 2497–508.
Thall PF, Simon R, Ellenberg SS. A two-stage design for choosing among several experimental treatments and a control in clinical trials. Biometrics 1988; 45: 537–47.
Thall PF, Simon R, Ellenberg SS. Two-stage selection and testing designs for comparative clinical trials. Biometrika 1989; 75: 303–10.
Schaid DJ, Wieand S, Therneau TM. Optimal two-stage screening designs for survival comparisons. Biometrika 1990; 77: 507–13.
Jennison C, Turnbull BW. Confirmatory seamless phase II/III clinical trials with hypotheses selection at interim: opportunities and limitations. Biometrical Journal 2006; 48: 650–55.
Stallard N, Friede T. Flexible group-sequential designs for clinical trials with treatment selection. Statistics in Medicine 2008; 27: 6209–27.
Posch M, Koenig F, Branson M, Brannath W, Dunger-Baldauf C, Bauer P. Testing and estimation in flexible group sequential designs with adaptive treatment selection. Statistics in Medicine 2005; 24: 3697–714.
Jennison C, Turnbull BW. Repeated confidence intervals for group sequential trials. Controlled Clinical Trials 1984; 5: 33–45.
Jennison C, Turnbull BW. Interim analyses: the repeated confidence interval approach. Journal of the Royal Statistical Society, Series B 1989; 51: 305–61.
Todd S, Stallard N. A new clinical trial design combining phases II and III: Sequential designs with treatment selection and a change of endpoint. Drug Information Journal 2005; 39: 109–18.
Friede T, Stallard N. A comparison of methods for adaptive treatment selection. Biometrical Journal 2008; 50: 767–81.
Burman C-F, Sonesson C. Are flexible designs sound? Biometrics 2006; 62: 664–9.
Bauer P, Posch M. Letter to the editor: modification of the sample size and the schedule of interim analyses in survival trials based on data inspections. Statistics in Medicine 2004; 23: 1333–35.
Stallard N. A confirmatory seamless phase II/III clinical trial design incorporating short-term endpoint information. Statistics in Medicine 2010; 29: 959–971.
Stallard N, Todd S, Whitehead J. Estimation following selection of the largest of two normal means. Journal of Statistical Planning and Inference 2008; 135: 402–19.
Bauer P, Koenig F, Brannath W, Posch M. Selection and bias – two hostile brothers. Statistics in Medicine 2009; 29: 1–13.
Shen L. An improved method of evaluating drug effect in a multiple dose clinical trial. Statistics in Medicine 2001; 20: 1913–29.
Stallard N, Todd S. Point estimates and confidence regions for sequential trials involving selection. Journal of Statistical Planning and Inference 2005; 135: 402–19.
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Article first published online: August 19, 2010
Issue published: December 2011
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PubMed: 20724313
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This article was published in Statistical Methods in Medical Research.
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