Sample Size Adjustment in Clinical Trials for Proving Equivalence

  • 5 Citations


To overcome the problem of uncertainty in the planning phase of clinical trials, study designs have been proposed that allow for mid-course reestimation of the sample size. Using a study in asthma patients, we illustrate how blind sample size adjustment can be performed in an equivalence trial. Thereby, we demonstrate how the type I error rate can be controlled. Further, we show that the well-known expectation-maximization algorithm-based procedure by Gould and Shih is inappropriate for the purpose of sample size reestimation.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 189

This is the net price. Taxes to be calculated in checkout.


  1. 1.

    Bauer P, Köhne K. Evaluation of experiments with adaptive interim analyses. Biometrics. 1994;50:1029–1104. Correction in Biometrics. 1996;52:380.

  2. 2.

    Wittes J, Brittain E. The role of internal pilot studies in increasing the efficiency of clinical trials. Stat Med. 1990;9:65–72.

  3. 3.

    Shun Z, Yuan W, Grady WE, Hsu H. Type I error in sample size re-estimations based on observed treatment difference. Stat Med. 2001;20:497–513.

  4. 4.

    Shih WJ. Commentary: Sample size re-estimation—journey for a decade. Stat Med. 2001;20:515–518.

  5. 5.

    Shun Z. Sample size reestimation in clinical trials. Drug Inf J. 2001;35.

  6. 6.

    Gould AL, Shih WJ. Sample size re-estimation without unblinding for normally distributed outcomes with unknown variance. Commun Stat—Theory Methods (B). 1992;21:2833–2853.

  7. 7.

    Committee for Proprietary Medicinal Products (CPMP). Replacement of Chlorofluorocarbons (CFCs) in metered dose inhalation products. CPMP Note for Guidance III/5378/93 Final. Brussels, Belgium: Commission of the European Communities; 1993.

  8. 8.

    Kunkel G, Schlaefke S, Koehler S. Efficacy, safety and acceptance of beclomethasone dipropionate (BDP) administered via a new dry powder inhaler or standard CFC metered dose inhaler in asthma patients. European Respiratory J. 1999; 14 (Suppl 30): 105s (Abstract).

  9. 9.

    Kieser M, Hauschke D. Approximate sample sizes for testing hypotheses about the ratio and difference of two means. J Biopharm Stat. 1999;9:641–650.

  10. 10.

    Hauschke D, Kieser M, Diletti E, Burke M. Sample size determination for proving equivalence based on the ratio of two means for normally distributed data. Stat Med. 1999;18:93–105.

  11. 11.

    Kieser M, Friede T. Blinded sample size reestimation in multiarmed clinical trials. Drug Inf J. 2000;34:455–460.

  12. 12.

    Sandvik L, Erikssen J, Mowinckel P, Rodland EA. A method for determining the size of internal pilot studies. Stat Med. 1996;15:1587–1590.

  13. 13.

    Singer J. Letter to the editor: A method for determining the size of internal pilot studies. Stat Med. 1999;18:1151–1153.

  14. 14.

    Birkett MA, Day SJ. Internal pilot studies for estimating sample size. Stat Med. 1994;13:2455–2463.

  15. 15.

    CPMP Working Party on Efficacy of Medicinal Products. Biostatistical methodology in clinical trials in applications for marketing authorizations for medicinal products. Stat Med. 1995;14:659–1682.

  16. 16.

    International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline: Statistical Principles for Clinical Trials. Stat Med. 1999;18:1905–1942.

  17. 17.

    Friede T, Kieser M. A comparison of methods for adaptive sample size adjustment. Stat Med. 2001.

  18. 18.

    Zucker DM, Wittes JT, Schabenberger O, Brittain E. Internal pilot studies II: comparison of various procedures. Stat Med. 1999;18:3493–3509.

  19. 19.

    Friede T, Kieser M. On the inappropriateness of an EM algorithm based procedure for blinded sample size reestimation. Stat Med. 2001.

  20. 20.

    Coffey CS, Muller KE. Exact test size and power of a gaussian error linear model for an internal pilot study. Stat Med. 1999;18:1199–1214.

  21. 21.

    Denne JS, Jennison C. Estimating the sample size for a t-test using an internal pilot. Stat Med. 1999;18:1575–1585.

  22. 22.

    Wittes J, Schabenberger O, Zucker D, Brittain E, Proschan M. Internal pilot studies I: type I error rate of the naive t-test. Stat Med. 1999;18:3481–3491.

  23. 23.

    Kieser M, Friede T. Re-calculating the sample size in internal pilot study designs with control of the type I error rate. Stat Med. 2000;19:901–911.

Download references

Author information

Correspondence to Dr. Meinhard Kieser PhD.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Friede, T., Kieser, M. Sample Size Adjustment in Clinical Trials for Proving Equivalence. Ther Innov Regul Sci 35, 1401–1408 (2001) doi:10.1177/009286150103500436

Download citation

Key Words

  • Interim analysis
  • Sample size review
  • Sample size adjustment
  • Equivalence trial
  • Control of the type I error rate