How Biased Are Indirect Comparisons, Particularly When Comparisons Are Made Over Time in Controlled Trials?


Indirect comparisons are undertaken when a comparison is made between two regimens, usually where the regimens have never been given concurrently in any controlled trial investigating the same general patient population. We highlight the issues of making indirect comparisons when there has been a period of time between the studies, particularly when indirect comparison is being made to placebo. We discuss the impact of any bias in indirectly estimating any effect over placebo in context with noninferiority trials.

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  1. 1.

    Hasselblad V, Kong DF. Staiistical methods fur comparison to placebo in active-control trials. Drug Inf J. 2001;25:435–449.

  2. 2.

    Lim E, Ali Z, Ali A, et al. Indirect comparison meta-analysis of aspirin therapy after coronary surgery. Br Med J. 2003;327:1309–1313.

  3. 3.

    Song F, Altman DG, Glenny AM, Deeks JJ. Validity of indirect comparison for estimating efficacy of competing interventions; empirical evidence from published meta-analyses. Br Med J. 2003: 326:472.

  4. 4.

    Wang SJ, Hung HMJ, Tsong Y. Non-inferiority analysis in active controlled trials. Encyclopaedia of Biopharmaceutical Statistics, 2nd ed. New York: Marcel Dekker; 2003:674–677.

  5. 5.

    D’Agostino RB, Massaro J, Sullivan LM. Non-inferiority trials: design concepts and issues—the encounters of academic consultants in statistics. Stat Med. 2003;22:169–186.

  6. 6.

    Wang SJ, Hung HMJ, Tsong Y. Utility and pitfalls of some statistical methods in active controlled trials. Control Clin Trials. 2002;23:15–28.

  7. 7.

    Snapinn SM. Alternatives for discounting in the analysis of non-inferiority trials. J Biopharm Stat. 2004;14:263–273.

  8. 8.

    Bech P. Meta analysis of placebo controlled trials with mirtazipine using core items of the Hamilton depression scale as evidence of pure anti-depressive effect in the short term treatment of major depression. Int J Neuropsychopharmacol. 2001;4:337–345.

  9. 9.

    Furukawa T, McGuire H, Barbui C. Low dosage tricyclic antidepressants for depression. Cochrane Database. 2003.

  10. 10.

    Wilson K, Motram P. Svanranthan P, Nightingale A. Antidepressants versus placebo for the depressed elderly. Cochrane Database. 2003.

  11. 11.

    Hazell P, O’Connel D, Heathcote D, Henry D. Tricyclic drugs Tor depression in children and adolescents. Cochrane Database. 2003.

  12. 12.

    Walsh BT, Sneidman SN, Sysko R, Gould M. Placebo response in studies of major depression, variable, substantial and growing. JAMA. 2002;14: 1840–1847.

  13. 13.

    McClung C, Quessy S, Julious S, Segretti A, Blum D. Placebo response rates in geographical location in COX-2 inhibitor trials of rheumatoid arthritis (RA) and osteoarthritis (OA). Paper presented at American College of Rheumatology Conference. San Antonio, 2004.

  14. 14.

    CHMP. Points to consider on switching between superiority and non-inferiority. Doc CPMP/EWP/482/99. 2000. Available at: Accessed April 14, 2008.

  15. 15.

    ICH E10. Choice of control group in clinical trials. 2000. Available at: Accessed April 14, 2008.

  16. 16.

    Jones B, Jarvis P, Lewis JA, Ebbutt AF. Trials to assess equivalence: the importance of rigorous methods. Br Med J. 1996;313:36–39.

  17. 17.

    Hung HMJ, Wang SJ, Lawrence J, O’Neil RT. Some fundamental issues with non-inferiority testing in active controlled trials. Stat Med. 2003;22:213–225.

  18. 18.

    Wiens BL. Choosing an equivalence limit for non-inferiority and/or equivalence studies. Control Clin Trials. 2002;23:2–14.

  19. 19.

    CHMP. Guideline on the choice of non-inferiority margin. Doc CPMP/EWP/2158/99. 2005. Available at: Accessed April 14. 2008.

  20. 20.

    Julious SA. Tutorial in biostatistics: sample sizes for clinical trials with normal data. Stat Med. 2004;23:1921–1986.

  21. 21.

    Wang SJ, Hung HMJ, TACT method for non-inferiority testing in active controlled trials. Stat Med. 2003;22:227–238.

  22. 22.

    Datta S, Halloran ME, Longini IM. Augmented HIV vaccine trial design for estimating reduction in infectiousness and protective efficacy. Stat Med. 1998;17:185–200.

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Correspondence to Steven A. Julious.

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The views expressed in this article are the professional views of the author and do not necessarily reflect the official position of the US food and Drug Administration.

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Julious, S.A., Wang, S. How Biased Are Indirect Comparisons, Particularly When Comparisons Are Made Over Time in Controlled Trials?. Ther Innov Regul Sci 42, 625–633 (2008) doi:10.1177/009286150804200610

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Key Words

  • Clinical trials
  • Indirect comparisons
  • Noninferiority
  • Placebo creep