Advertisement

Noninferiority Trial Design

  • Mark Chang
Chapter
  • 2.9k Downloads
Part of the Statistics for Biology and Health book series (SBH)

Abstract

Superiority and noninferiority (NI) trials are two common types of clinical trials. Superiority means, in layman’s language, that the test drug is better than the comparative drug (active comparator or active-control), whereas noninferiority suggests that the test drug may not be as good as the comparative drug, but the difference is not clinically significant. If a test drug is noninferior to an active-control, it must be at least superior to a placebo (Fig. 3.1).

Keywords

Test Drug Draft Guidance Superiority Trial Noninferiority Trial Noninferiority Margin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Further Readings and References

  1. Brittain, E., Hu, Z.: Noninferiority trial design and analysis with an ordered three-level categorical endpoint. J. Biopharm. Stat. 19, 685–699 (2009)CrossRefMathSciNetGoogle Scholar
  2. Chan, I.S.F.: Power and sample size determination for noninferiority trials using an exact method. J. Biopharm. Stat. 12(4), 457–469 (2002)CrossRefGoogle Scholar
  3. Chang, M.: Multiple-arm superiority and noninferiority designs with various endpoints. Pharm. Stat. 6, 43–52 (2007a)CrossRefGoogle Scholar
  4. Chang, M.: Adaptive Design Theory and Implementation Using SAS and R. Chapman & Hall/CRC, Boca Raton (2007b)Google Scholar
  5. Chang, M.: Monte Carlo Simulation for the Pharmaceutical Industry. Chapman and Hall/CRC, Raton (2010)CrossRefGoogle Scholar
  6. CHMP: Points to consider on switching between superiority and noninferiority. Br. J. Clin. Pharm. 52, 223–228 (2001)Google Scholar
  7. CHMP: Guideline on the choice of the noninferiority margin, EMEA/EWP/2158/99. London, July 27, 2005 (2005)Google Scholar
  8. Chow, S.C., Shao, J.: On noninferiority margin and statistical tests in active control trials. Stat. Med. 25, 1101–1113 (2005)CrossRefMathSciNetGoogle Scholar
  9. Cook, R.J., Lee, K.A., Li, H.: Noninferiority trial design for recurrent events. Stat. Med. 26, 4563–4577 (2007)CrossRefMathSciNetGoogle Scholar
  10. CPMP: Points to consider on switching between superiority and non-inferiority. www.ema. europa.eu (2000). Accessed 18 May 2010
  11. D’Agostino, R.B.: Editoral, noninferiority trials: Advances in concepts and methodology. Stat. Med. 22, 165–167 (2003)CrossRefGoogle Scholar
  12. D’Agostino, R.B., Massaro, J.M., Sullivan, L.M.: Noninferiority trials: Design concepts and issues-the encounters of academic consultants in statistics. Stat. Med. 22, 169–186 (2003)CrossRefGoogle Scholar
  13. Dunnett, C.W., Gent, M.: An alternative to the use of two-sided tests in clinical trials. Stat. Med. 15, 1729–1738 (1976)CrossRefGoogle Scholar
  14. Dunnett, C.W., Gent, M.: Significant testing to establish equivalence between treatments with special reference to data in the form of 2 ×2 tables. Biometrics 33, 593–602 (1977)CrossRefGoogle Scholar
  15. Ellenberg, S.S., Temple, R.: Placebo-controlled trials and active controlled trials in the evaluation of new treatment. Part 2: Practical issues and specific cases. Ann. Intern. Med. 133, 464–470 (2000)Google Scholar
  16. Farrington, C.P., Manning, G.: Test statistics and sample size formulae for comparative binomial trials with null hypothesis of non-zero risk difference or non-unity relative risk. Stat. Med. 9, 1447–1454 (1990)CrossRefGoogle Scholar
  17. FDA: International Conference on Harmonisation. Statistical Principles for Clinical Trials (ICH E 9). Food and Drug Administration, Department of Health and Human Services, Washingtom (1998)Google Scholar
  18. FDA: Guidance for Industry Non-Inferiority Clinical Trials (draft). Food and Drug Administration, Department of Health and Human Services, Washingtom (2010)Google Scholar
  19. Fleming, T.R.: Current issues in noninferiority trials. Stat. Med. 27, 317–332 (2008)CrossRefMathSciNetGoogle Scholar
  20. Hung, H.M., Wang, S.J., O’Neill, R.T.: Issues with statistical risks for testing methods in noninferiority trial without a placebo arm. J. Biopharm. Stat. 17(2), 201–213 (2007)CrossRefMathSciNetGoogle Scholar
  21. Ioannidis, J.P.A.: Why most published research findings are false. PLoS Med. 2(8), e124 (2005)CrossRefGoogle Scholar
  22. Kieser, M., Friede, T.: Planning and analysis of three-arm non-inferiority trials with binary endpoints. Stat. Med. 26, 253–273 (2007)CrossRefMathSciNetGoogle Scholar
  23. Liu, J.P., Hsueh, H.M., Hsieh, E., Chen, J.J.: Tests for equivalence or noninferiority for paired binary data. Stat. Med. 21, 231–245 (2002)CrossRefGoogle Scholar
  24. Koch, G.G.: Commentory, comments on ‘Current issues in noninferiority trials’. Stat. Med. 27, 333–342 (2008)CrossRefMathSciNetGoogle Scholar
  25. Kong, L., Kohberger, R.C., Koch, G.G.: Type I error and power in noninferiority/equivalence trials with correlated multiple endpoints: An example from vaccine development trials. J. Biopharm. Stat. 14, 893–907 (2004)CrossRefMathSciNetGoogle Scholar
  26. Koyama, T., Westfall, P.H.: Decision-theoretic views on simultaneous testing of superiority and noninferiority. J. Biopharm. Stat. 15, 943–955 (2005)CrossRefMathSciNetGoogle Scholar
  27. Lu, Y., Jin, H., Genant, H.K.: On the noninferiority of a diagnostic test based on paired observations. Stat. Med. 22, 3029–3044 (2003)CrossRefGoogle Scholar
  28. Morikawa, T., Yoshida, M.: A useful testing strategy in phase III trials: Combined test of superiority and test of equivalence. J. Biopharm. Stat. 5, 297–306 (1995)CrossRefGoogle Scholar
  29. Nam, J.: Establishing equivalence of two treatments and sample size requirements in matched-pairs design. Biometrics 53, 1422–1430 (1997)zbMATHCrossRefGoogle Scholar
  30. Nam, J., Kwon, D.: Noninferiority tests for clustered matched-pair data. Stat. Med. 28, 1668–1679 (2009)CrossRefMathSciNetGoogle Scholar
  31. Ng, T.H.: Issues of simultaneous tests for noninferiority and superiority, with discussions. J. Biopharm. Stat. 13, 629–639 (2003)zbMATHCrossRefGoogle Scholar
  32. Ng, T.H.: Simultaneous testing of noninferiority and superiority increases the false discovery rate. J. Biopharm. Stat. 17, 259–264 (2007)CrossRefGoogle Scholar
  33. PAREXEL: Parexel’s Bio/Pharmaceutical R&D Statistical Sourcebook 2007/2008. PAREXEL, Waltham (2008)Google Scholar
  34. Pearlman, J.B.: The commercialization of medicine. http://www.google.com (2007). Accessed 10 Sep 2009
  35. Pigeot, I., Schäfer, J., Röhmel, J., Hauschke, D.: Assessing noninferiority of a new treatment in a three-arm clinical trial including a placebo. Stat. Med. 22, 883–899 (2003)CrossRefGoogle Scholar
  36. Rothmann, M., Li, N., Chen, G., Chi1, G.Y.H., Temple, R., Tsou, H.H.: Design and analysis of noninferiority mortality trials in oncology. Stat. Med. 22, 239–264 (2003)Google Scholar
  37. Shao, J.: Mathematical Statistics. Springer, New York, NY (2003)zbMATHCrossRefGoogle Scholar
  38. Sidik, K.: Exact unconditional tests for testing noninferiority in matched-pairs design. Stat. Med. 22, 265–278 (2003)CrossRefGoogle Scholar
  39. Siqueira, A.L., Whitehead, A., Todd, S.: Active-control trials with binary data: A comparison of methods for testing superiority or noninferiority using the odds ratio, with comments. Stat. Med. 27, 353–370 (2008)CrossRefMathSciNetGoogle Scholar
  40. Snapinn, S., Jiang, Q.: Correction. Stat. Med. 27, 4855–4856 (2008)CrossRefMathSciNetGoogle Scholar
  41. Tang, M.L., Tang, N.S.: Tests of noninferiority via rate difference for three-arm clinical trials with placebo. J. Biopharm. Stat. 14, 337–347 (2004)CrossRefGoogle Scholar
  42. Tango, T.: Equivalence test and confidence interval for the difference in proportions for the paired-sample design. Stat. Med. 17, 891–908 (1998)CrossRefGoogle Scholar
  43. Temple, R.: Active control noninferiority studies: Theory, assay sensitivity, choice of margin. FDA presentation. www.FDA.gov (2002). Accessed 19 Feb 2002
  44. Temple, R., Ellenberg, S.S.: Placebo-controlled trials and active-controlled trials in the evaluation of new treatments. Part 1: Ethical and scientific issues. Ann. Intern. Med. 133, 455–463 (2000)Google Scholar
  45. Tsong, Y., Chen, W.J.: Noninferiority testing beyond simple two-sample comparison. J. Biopharm. Stat. 17, 289–308 (2007)CrossRefMathSciNetGoogle Scholar
  46. Wang, Y.C., Chen, G., Chi, G.Y.H.: A ratio test in active control non-inferiority trials with time-to-event endpoint. J. Biopharm. Stat. 16, 151–164 (2006)CrossRefMathSciNetGoogle Scholar
  47. Wang, S.J., Hung, H.M., Tsong, Y., Cui, L.: Group sequential test strategies for superiority and noninferiority hypotheses in active controlled clinical trials. Stat. Med. 20, 1903–1912 (2001)CrossRefGoogle Scholar
  48. Wiens, B.L., Heyes, J.F.: Testing for interactions in studies of noninferiority. J. Biopharm. Stat. 13, 103–115 (2003)zbMATHCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Mark Chang
    • 1
  1. 1.BiometricsAMAG Pharmaceuticals, Inc.LexingtonUSA

Personalised recommendations