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Designing, Monitoring, and Analyzing Group Sequential Clinical Trials Using the RCTdesign Package for R

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Proceedings of the Fourth Seattle Symposium in Biostatistics: Clinical Trials

Part of the book series: Lecture Notes in Statistics ((LNSP,volume 1205))

Abstract

The use of group sequential methodology has become widespread in the conduct of clinic trials. As each clinical trial presents unique scientific, statistical, and logistical constraints, it is important to carefully evaluate candidate group sequential designs to ensure desirable operating characteristics. At the implementation stage of a clinical trial design it is also essential to account for deviations from original design specifications in order to control operating characteristics such as type I and II error rates. These changes might include the number and/or timing of analyses as well as deviations from the originally assumed variability of outcome measures. Due to the computational complexity involved in evaluating, monitoring, and analyzing a group sequential procedure, specialized software is required. In this manuscript we demonstrate how the RCTdesign package (http://www.rctdesign.org) in R can be used to select, implement, and analyze a group sequential stopping rule. Throughout, we illustrate trial design and monitoring in the context of a group sequential survival trial of an experimental monoclonal antibody in patients with relapsed chronic lymphocytic leukemia (CLL).

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References

  1. Boyd A, Kittelson J, Gillen D (2012) Estimation of treatment effect under nonproportional hazards and covariate dependent censoring. Stat Med [Epub ahead of print]

    Google Scholar 

  2. Brummel S, Gillen D (2012) Flexibly monitoring group sequential survival trials using constrained boundaries. Revised for Journal of Biopharmaceutical Statistics

    Google Scholar 

  3. Burington BE, Emerson SS (2003) Flexible implementations of group sequential stopping rules using constrained boundaries. Biometrics 59:770–777

    Google Scholar 

  4. Cytel Software Corporation (2000) EaSt. A software package for the design and interim monitoring of group-sequential clinical trials. Cambridge, Mass

    Google Scholar 

  5. Emerson SS (2006) Issues in the use of adaptive clinical trial designs. Stat Med 25:3270–3296

    Google Scholar 

  6. Emerson SS, Fleming TR (1989) Symmetric group sequential test designs. Biometrics 45: 905–923

    Google Scholar 

  7. Emerson SS, Fleming TR (1990) Parameter estimation following group sequential hypothesis testing. Biometrika 77:875–892

    Google Scholar 

  8. Emerson SS, Kittelson JM, Gillen DL (2007) Bayesian evaluation of group sequential designs. Stat Med 26:1431–1449

    Google Scholar 

  9. Emerson SS, Kittelson JM, Gillen DL (2007) Frequentist evaluation of group sequential designs. Stat Med 26:5047–5080

    Google Scholar 

  10. Fisher LD (1998) Self-designing clinical trials. Stat Med 17:1551–1562

    Google Scholar 

  11. Fleming TR, Harrington DP (1991) Counting processes and survival analysis. Wiley, New York

    Google Scholar 

  12. Gillen DL (2009) A random walk approach for quantifying uncertainty in group sequential survival trials. Comput Stat Data Anal 53(3):603–620

    Google Scholar 

  13. Gillen DL, Emerson SS (2005) Information growth in a family of weighted logrank statistics under repeated analysis. Seq Anal 24(1):1–22

    Google Scholar 

  14. Gillen DL, Emerson SS (2005) A note on P-values under group sequential testing and nonproportional hazards. Biometrics 61(2):546–551

    Google Scholar 

  15. Gillen DL, Emerson SS (2007) Non-transitivity in a class of weighted logrank statistics under non-proportional hazards. Stat Probab Lett 77(2):123–130

    Google Scholar 

  16. Gillen DL, Emerson SS (2011) Evaluating a group sequential design in the setting of non-proportional hazards UW Biostatistics Working Paper Series. Working Paper 307. http://biostats.bepress.com/uwbiostat/paper307

  17. Kittelson JM, Emerson SS (1999) A unifying family of group sequential test designs. Biometrics 55:874–882

    Google Scholar 

  18. Lan KKG, DeMets DL (1983) Discrete sequential boundaries for clinical trials. Biometrika 70:659–663

    Google Scholar 

  19. Liu A, Hall WJ (1999) Unbiased estimation following a group sequential test. Biometrika 86:71–78

    Google Scholar 

  20. Nguyen V, Gillen D (2012) Robust inference in semiparametric discrete hazard models for observational studies. Revised for Journal of the American Statistical Association

    Google Scholar 

  21. Nguyen V, Gillen D (2012) Robust inference in semiparametric discrete hazard models for randomized clinical trials. Lifetime Data Anal 18:446–69

    Google Scholar 

  22. O’Brien PC, Fleming TR (1979) A multiple testing procedure for clinical trials. Biometrics 35:549–556

    Google Scholar 

  23. Pampallona S, Tsiatis A, Kim K (1995) Spending functions for the type i and type ii error probabilities of group sequential tests. Technical report. http://76.12.5.166/papers/usefun.pdf

  24. PEST (2000) Planning and evaluation of sequential trials. The MPS Research Unit, The University of Reading, Reading

    Google Scholar 

  25. Pocock SJ (1977) Group sequential methods in the design and analysis of clinical trials. Biometrika 64:191–200

    Google Scholar 

  26. Proschan MA, Hunsberger SA (1995) Designed extension of studies based on conditional power. Biometrics 51:1315–1324

    Google Scholar 

  27. SAS Institute Inc (2005) SAS OnlineDoc 9.1.3, SAS/SEQDESIGN, Cary, NC

    Google Scholar 

  28. TIBCO Software Inc (2000) S-Plus SeqTrial. Palo Alto, Ca

    Google Scholar 

  29. Struthers CA, Kalbfleisch JD (1986) Misspecified proportional hazard models. Biometrika 73:363–369

    Google Scholar 

  30. Tsiatis AA, Mehta CR (2003) On the inefficiency of the adaptive design for monitoring clinical trials. Biometrika 90:367–378

    Google Scholar 

  31. Tsiatis AA, Rosner GL, Mehta CR (1984) Exact confidence intervals following a group sequential test. Biometrics 40:797–803

    Google Scholar 

  32. Wang SK, Tsiatis AA (1987) Approximately optimal one-parameter boundaries for group sequential trials. Biometrics 43:193–199

    Google Scholar 

  33. Whitehead J (1986) On the bias of maximum likelihood estimation following a sequential test. Biometrika 73:573–581

    Google Scholar 

  34. Whitehead J (1986) Supplementary analysis at the conclusion of a sequential clinical trial. Biometrics 42:461–471

    Google Scholar 

  35. Whitehead J (1997) The design and analysis of sequential clinical trials. Wiley, New York

    Google Scholar 

  36. Whitehead J, Stratton I (1983) Group sequential clinical trials with triangular continuation regions. Biometrics 39:227–236 (corr: V39 p1137)

    Google Scholar 

  37. Xu R, O’Quigley J (2000) Estimating average regression effect under non-proportional hazards. Biostatistics (Oxford) 1(4):423–439

    Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Statistics, University of California, 2226 Donald Bren Hall, Irvine, CA, 92697-1250, USA

    Daniel L. Gillen

  2. Department of Biostatistics, University of Washington, Seattle, WA, USA

    Scott S. Emerson

Authors
  1. Daniel L. Gillen
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  2. Scott S. Emerson
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Corresponding author

Correspondence to Daniel L. Gillen .

Editor information

Editors and Affiliations

  1. University of Washington, Department of Biostatistics, Seattle, 98195-7232, Washington, USA

    Thomas R. Fleming

  2. University of Washington, Department of Biostatistics, Seattle, 98195-7232, Washington, USA

    Bruce S. Weir

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Gillen, D.L., Emerson, S.S. (2013). Designing, Monitoring, and Analyzing Group Sequential Clinical Trials Using the RCTdesign Package for R. In: Fleming, T., Weir, B. (eds) Proceedings of the Fourth Seattle Symposium in Biostatistics: Clinical Trials. Lecture Notes in Statistics(), vol 1205. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5245-4_11

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