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Clinical Trials with an Adaptive Choice of Hypotheses

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Abstract

In a clinical trial with an adaptive interim analysis it is possible to modify not only the design, but even the hypothesis(es) of interest, in a formally correct manner. Two examples of clinical trials are described where modifications of hypotheses are based on substantial scientific reasons. Generally, it is emphasized that the danger of manipulation caused by flexible designs must be controlled by very restrictive guidelines.

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References

  1. 1.

    Armitage P. Sequential Medical Trials. Oxford, England: Blackwell; 1975.

  2. 2.

    Pocock SJ. Group sequential methods in the design and analysis of clinical trials. Biometrika. 1977;64: 191–199.

  3. 3.

    Pampallona S, Tsiatis AA. Group sequential designs for one-sided and two-sided hypothesis testing with provision for early stopping in favour of the null hypothesis. J Stat Plann Inf. 1994;42:19–35.

  4. 4.

    Jennison C, Turnbull BW. Group Sequential Methods with Applications to Clinical Trials. Boca Raton, FL: Chapman & Hall; 1999.

  5. 5.

    Bauer P. Multistage testing with adaptive designs. Biom Inf Med Biol. 1989;20:130–136.

  6. 6.

    Muller HH, Schafer H. Adaptive group sequential designs for clinical trials: combining the advantages of adaptive and of classical group sequential approaches. Biometrics. 2001;57:Forthcoming.

  7. 7.

    Bauer P, Kohne K. Evaluation of experiments with adaptive interim analyses. Biometrics. 1994;50: 1029–1041.

  8. 8.

    Fisher RA. Statistical Methods for Research Workers. London, England: Oliver & Boyd; 1932.

  9. 9.

    Bauer P, Rohmel J. An adaptive method for establishing a dose-response relationship. Stat Med. 1995;14: 1595–1607.

  10. 10.

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

  11. 11.

    Wassmer G. Statistical Test Procedures for Group Sequential and Adaptive Designs in Clinical Trials. Koln, Germany: Verlag Alexander Mönch; 1999.

  12. 12.

    Wassmer G, Eisebitt R, Coburger S. Flexible interim analyses in clinical trials using multistage adaptive test designs. Drug Inf J. 2001.

  13. 13.

    Lehmacher W, Wassmer G. Adaptive sample size calculations in group sequential trials. Biometrics. 1999;55:1286–1290.

  14. 14.

    Hochberg Y, Tamhane AC. Multiple Comparison Procedures. New York, NY: Wiley; 1987.

  15. 15.

    Marcus R, Peritz E, Gabriel KR. On closed testing procedures with special reference to ordered analysis of variance. Biometrika. 1976;63:655–660.

  16. 16.

    Holm S. A simple sequentially rejective multiple test procedure. Scand J Stat. 1979;6:65–70.

  17. 17.

    Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika. 1988;75: 800–803.

  18. 18.

    Hommel G. A stagewise rejective multiple test procedure based on a modified Bonferroni test. Biometrika. 1988;75:383–386.

  19. 19.

    Tang DI, Geller NL. Closed testing procedures for group sequential clinical trials with multiple end-points. Biometrics. 1999;55:1188–1192.

  20. 20.

    Kieser M, Bauer P, Lehmacher W. Inference on multiple endpoints in clinical trials with adaptive interim analyses. Biom J. 1999;41:261–277.

  21. 21.

    Bauer P, Kieser M. Combining different phases in the development of medical treatments within a single trial. Stat Med. 1999;18:1833–1848.

  22. 22.

    Hommel G. Adaptive modifications of hypotheses after an interim analysis. Biom J. 2001;43:in press.

  23. 23.

    Posch M, Bauer P. Adaptive two stage designs and the conditional error function. Biom J. 1999;41:689–696.

  24. 24.

    Hommel G. Multiple test procedures for arbitrary dependence structures. Metrika. 1986;33:321–336.

  25. 25.

    Bauer P, Rohmel J, Maurer W, Hothorn L. Testing strategies in multi-dose experiments including active control. Stat Med. 1998;17:2133–2146.

  26. 26.

    Kropf S, Hommel G, Schmidt U, Brickwedel J, Jensen MS. Multiple comparisons of treatments with stable multivariate tests in a two-stage adaptive design, including a test for non-inferiority. Biom J. 2000;42:951–965.

  27. 27.

    O’Brien PC. Procedures for comparing samples with multiple endpoints. Biometrics. 1984;40:1079–1087.

  28. 28.

    Lauter J. Exact t and F tests for analyzing studies with multiple endpoints. Biometrics. 1996;52:964–970.

  29. 29.

    Lauter J, Glimm E, Kropf S. New multivariate tests for data with an inherent structure. Biom J. 1996;38:5–22. Erratum: Biom J. 1998;40:1015.

  30. 30.

    Lauter J, Glimm E, Kropf S. Multivariate tests based on left-spherically distributed linear scores. Ann Statist. 1998;26:1972–1988. Erratum: Ann Statist. 1999;27:1441.

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Correspondence to Gerhard Hommel PhD.

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Hommel, G., Kropf, S. Clinical Trials with an Adaptive Choice of Hypotheses. Ther Innov Regul Sci 35, 1423–1429 (2001) doi:10.1177/009286150103500438

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Key Words

  • Adaptive design
  • Group-sequential design
  • Closure test
  • Multiple endpoints; A priori ordered hypotheses