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Issues in the design and analysis of AIDS clinical trials

  • Dennis O. Dixon
  • Jeffrey M. Albert
Part of the Cancer Treatment and Research book series (CTAR, volume 75)

Abstract

The AIDS epidemic has provoked a massive response from the worldwide scientific community. To address the need for rapid evaluation of new treatments for the primary viral infection and related opportunistic infections, malignancies, and other illnesses, the Federal Government established the largest publicly-sponsored program of clinical trials ever undertaken. As intended, these resources made it possible to enlist many gifted academic and government scientists in the effort, including biostatisticians and other clinical trialists. There have been advances in connection with several aspects of clinical trial design and analysis, and the body of this chapter highlights a few of these. Before beginning, however, we consider the question of why it is necessary, or at least useful, to focus on advances in methodology for AIDS clinical trials.

Keywords

Human Immunodeficiency Virus Surrogate Endpoint Human Immunodeficiency Virus Disease Symptomatic Human Immunodeficiency Virus Infection Asymptomatic Human Immunodeficiency Virus Infection 
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.

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References

  1. 1.
    Fauci AS (1993). The National Institutes of Health Five-Year Plan for HIV-Related Research. Office of AIDS Research: Washington, DC.Google Scholar
  2. 2.
    Byar DP, Schoenfeld DA, Green SB, et al. (1990). Design considerations for AIDS trials. N Engl J Med 323:1343–1348.PubMedCrossRefGoogle Scholar
  3. 3.
    Green SB, Ellenberg SS, Finkelstein DM, et al. (1990). Issues in the design of drug trials for AIDS. Controlled Clin Trials 11:80–87.PubMedCrossRefGoogle Scholar
  4. 4.
    Ellenberg SS, Cooper E, Eigo J, et al. (1992). Studying treatments for AIDS: new challenges for clinical trials. Controlled Clin Trials 13:272–292.PubMedCrossRefGoogle Scholar
  5. 5.
    Ellenberg SS, Finkelstein DM, Schoenfeld DA (1992). Statistical issues arising in AIDS clinical trials (with comments and rejoinder). J Am Stat Assoc 87:562–583.CrossRefGoogle Scholar
  6. 6.
    Dixon DO, Rida WN, Fast PE, Hoth DF (1993). HIV vaccine trials: Some design issues including sample size calculation. J AIDS 6:485–496.Google Scholar
  7. 7.
    Ellenberg SS, Dixon DO (1994). Statistical issues in designing clinical trials of AIDS treatments and vaccines. J Stat Planning Inf 42:123–135.CrossRefGoogle Scholar
  8. 8.
    Amato DA, Lagakos SW (1990). Considerations in the selection of end points for AIDS clinical trials. J AIDS 3 (Suppl 2):S64–S68.Google Scholar
  9. 9.
    Lagakos SW, Hoth DF (1992). Surrogate markers in AIDS: Where are we? Where are we going? Ann Intern Med 116:599–601.PubMedGoogle Scholar
  10. 10.
    Moss A (1990). Laboratory markers as potential surrogates for clinical outcomes in AIDS trials. J AIDS 3 (Suppl 2):S69–S71.Google Scholar
  11. 11.
    Mildvan D (1993). Clinical validation of virologic and immunologic assays. Presentation at the 17th AIDS Clinical Trials Group Meeting.Google Scholar
  12. 12.
    Machado SG, Gail MH, Ellenberg SS (1990). On the use of laboratory markers as surrogates for clinical endpoints in the evaluation of treatment for HIV infection. J AIDS 3:1065–1073.Google Scholar
  13. 13.
    Prentice RL (1989). Surrogate endpoints in clinical trials: Definition and operational criteria. Stat Med 8:431–440.PubMedCrossRefGoogle Scholar
  14. 14.
    Choi S, Lagakos SW, Schooley RT, Volberding PA (1993). CD4+ lymphocytes are an incomplete surrogate marker for clinical progression in persons with asymptomatic HIV infection taking zidovudine. Ann Intern Med 118:674–680.PubMedGoogle Scholar
  15. 15.
    Lin DY, Fischl MA, Schoenfeld DA (1993). Evaluating the role of CD4-lymphocyte counts as surrogate endpoints in human immunodeficiency virus clinical trials. Stat Med 12:835–842.PubMedCrossRefGoogle Scholar
  16. 16.
    DeGruttola V, Wulfsohn M, Fischl MA, Tsiatis A (1993). Modeling the relationship between survival and CD4-lymphocytes in patients with AIDS and AIDS-related complex. JAIDS 6:359–365.Google Scholar
  17. 17.
    Concorde Coordinating Committee (1994). Concorde: MRC/ANRS randomised, double-blind controlled trial of immediate and deferred zidovudine in symptom-free HIV infection. Lancet 343:871–881.CrossRefGoogle Scholar
  18. 18.
    Kosorok MR, Fleming TR (1993). Using surrogate failure time data to increase cost effectiveness in clinical trials. Biometrika 80:823–833.CrossRefGoogle Scholar
  19. 19.
    Fleming T, Prentice R, Pepe M, Glidden D (1994). Surrogate and auxiliary endpoints in clinical trials, with potential applications in cancer and AIDS research. Stat Med 13:955–968.PubMedCrossRefGoogle Scholar
  20. 20.
    Pepe MS (1992). Inference using surrogate outcome data and a validation sample. Biometrika 79:344–365.CrossRefGoogle Scholar
  21. 21.
    Pepe MS, Reilly M, Fleming TR (in press). Auxiliary outcome data and the mean score method. J Stat Planning Inference.Google Scholar
  22. 22.
    Finkelstein DM, Schoenfeld DA (1994). Analyzing survival in the presence of an auxiliary variable. Stat Med 13:1747–1754.PubMedCrossRefGoogle Scholar
  23. 23.
    Guyatt G, Feeny D, Patrick D (1991). Issues in quality-of-life measurement in clinical trials. Controlled Clin Trials 12 (Suppl):81S–90S.PubMedCrossRefGoogle Scholar
  24. 24.
    Fitzpatrick R, Fletcher A, Gore S, Jones D, Spiegelhalter D, Cox D (1992). Quality of life measures in health care. I: Applications and issues in assessment. Br Med J 305:1074–1077.CrossRefGoogle Scholar
  25. 25.
    Cox DR, Fitzpatrick R, Gore SM, Spiegelhalter DJ, Fletcher AE, Jones DR (1992). Quality-of-life assessment: can we keep it simple (with discussion)? J R Stat Soc A 155: 353–393.CrossRefGoogle Scholar
  26. 26.
    Williams JBW, Rabkin JG (1991). The concurrent validity of items in the quality of life index in a cohort of HIV-positive and HIV-negative gay men. Controlled Clin Trials 12 (Suppl):129S–141S.PubMedCrossRefGoogle Scholar
  27. 27.
    Spitzer WO, Dobson AJ, Hall J, Chesterman E, Levi J, Shepherd R, Battista RN, Catchlove BR (1981). Measuring the quality of life of cancer patients: a concise QL-index for use by physicians. J Chron Dis 34:585–597.PubMedCrossRefGoogle Scholar
  28. 28.
    Wu AW, Rubin HR, Mathews WC, Ware JE, Brysk LT, Hardy WD, Bozzette SA, Spector SA, Richman DD (1991). A health status questionnaire using 30 items from the medical outcomes study. Preliminary validation in persons with early HIV infection. Med Care 29:786–798.PubMedCrossRefGoogle Scholar
  29. 29.
    Glasziou PP, Simes RJ, Gelber RD (1990). Quality adjusted survival analysis. Stat Med 9:1259–1276.PubMedCrossRefGoogle Scholar
  30. 30.
    Gelber RD, Gelman RS, Goldhirsch A (1989). A quality of life oriented end point for comparing therapies. Biometrics 45:781–796.PubMedCrossRefGoogle Scholar
  31. 31.
    Fischl MA, Richman DD, Hansen N, et al. (1990). The safety and efficacy of zidovudine (AZT) in the treatment of subjects with mildly symptomatic human immunodeficiency virus type 1 (HIV) infection. Ann Intern Med 112:727–737.PubMedGoogle Scholar
  32. 32.
    Gelber RD, Lenderking WR, Cotton DJ, et al. (1992). Quality-of-life evaluation in a clinical trial of zidovudine therapy in patients with mildly symptomatic HIV infection. Ann Intern Med 116:961–966.PubMedGoogle Scholar
  33. 33.
    Volberding PA, Lagakos SW, Koch MA, et al. (1990). Zidovudine in asymptomatic human immunodeficiency virus infection. N Engl J Med 322:941–949.PubMedCrossRefGoogle Scholar
  34. 34.
    Lenderking WR, Gelber RD, Cotton DJ, Cole BF, Goldhirsch A, Volberding PA, Testa MA (1994). Evaluation of the quality of life associated with zidovudine treatment in asymptomatic human immunodeficiency virus infection. N Engl J Med 330:738–743.PubMedCrossRefGoogle Scholar
  35. 35.
    Sackett DL, Snow JC (1979). The magnitude of compliance and noncompliance. In Compliance in Health Care, RB Haynes, DW Taylor, DL Sackett (eds.). Baltimore, MD, The Johns Hopkins University Press, 11-22.Google Scholar
  36. 36.
    Schork MA, Remington RD (1967). The determination of sample size in treatment-control comparisons for chronic disease studies in which dropout or non-adherence is a problem. J Chron Dis 20:233–239.PubMedCrossRefGoogle Scholar
  37. 37.
    Lachin JM, Foulkes MA (1986). Evaluation of sample size and power for analysis of survival with allowance for nonuniform patient entry, losses to follow-up, noncompliance, and stratification. Biometrics 42:507–519.PubMedCrossRefGoogle Scholar
  38. 38.
    Peduzzi P, Wittes J, Detre K, Holford T (1993). Analysis as-randomized and the problem of non-adherence: an example for the Veterans Affairs randomized trial of coronary artery bypass surgery. Stat Med 12:1185–1195.PubMedCrossRefGoogle Scholar
  39. 39.
    Lee YJ, Ellenberg JH, Hirtz DG, Nelson KB (1991). Analysis of clinical trials by treatment actually received: is it really an option? Stat Med 10:1595–1506.PubMedCrossRefGoogle Scholar
  40. 40.
    May GS, DeMets DL, Friedman LM, et al. (1981). The randomized clinical trial: bias in analysis. Circulation 64:669–673.PubMedCrossRefGoogle Scholar
  41. 41.
    Coronary Drug Research Group (1980). Influence of adherence to treatment and response of cholesterol on mortality in the Coronary Drug Project. N Engl J Med 302:1038–1041.Google Scholar
  42. 42.
    Efron B, Feldman D (1991). Compliance as an explanatory variable in clinical trials. J Am Stat Assoc 86:9–26.CrossRefGoogle Scholar
  43. 43.
    Mark SD, Robins JM (1993). A method for the analysis of randomized trials with compliance information: an application to the multiple risk factor intervention trial. Controlled Clin Trials 14:79–97.PubMedCrossRefGoogle Scholar
  44. 44.
    Albert JM, DeMets DL (1994). On a model-based approach to estimating efficacy in clinical trials. Stat Med 13:2323–2335.PubMedCrossRefGoogle Scholar
  45. 45.
    Robins JM, Tsiatis AA (1991). Correcting for non-compliance in randomized trials using rank preserving structural failure time models. Commun Stat Theory Methods 20:2609–2631.CrossRefGoogle Scholar
  46. 46.
    Lagakos SW, Lim LL-Y, Robins JM (1990). Adjusting for early treatment termination in comparative clinical trials. Stat Med 9:1417–1424.PubMedCrossRefGoogle Scholar
  47. 47.
    Spilker B (1991). Guide to Clinical Trials. New York: Raven Press.Google Scholar
  48. 48.
    Lim LL-Y (1992). Estimating compliance to study medication from serum drug levels: application to an AIDS clinical trial of zidovudine. Biometrics 48:619–630.PubMedCrossRefGoogle Scholar
  49. 49.
    Richardson D, Liou S-H, Kahn JO (1993). Uric acid and didanosine compliance in AIDS clinical trials: an analysis of AIDS Clinical Trials Group protocols 116A and 116B/117. J AIDS 6:1212–1223.Google Scholar
  50. 50.
    Pritzker L, Ogus J, Hansen MH (1965). Computer editing methods -some applications and results. Proceedings 35th session, Belgrade. Bull Int Stat Inst 41:442–465.Google Scholar
  51. 51.
    Naus JI (1977). Data Quality Control and Editing. New York: Marcel Dekker.Google Scholar
  52. 52.
    Altmann L (1994). Report of fraud in a major breast cancer study. New York Times.Google Scholar
  53. 53.
    Deming WE (1986). Out of the Crisis. Cambridge, MA: Massachusetts Institute of Technology, Center for Advanced Engineering Study.Google Scholar
  54. 54.
    West M, Winkler R (1991). Data base error trapping and prediction. A focus on Bayesian methods. J Am Stat Assoc 86:987–996.CrossRefGoogle Scholar
  55. 55.
    Matthews JNS, Altman DG, Campbell MJ, Royston P (1990). Analysis of serial measurements in medical research. Br Med J 300:230–235.CrossRefGoogle Scholar
  56. 56.
    Frison L, Pocock S (1992). Repeated measures in clinical trials: analysis using mean summary statistics and its implications for design. Stat Med 11:1685–1704.PubMedCrossRefGoogle Scholar
  57. 57.
    Foulkes MA, Ellenberg SS (in preparation). Large simple trials of HIV therapies. In AIDS Clinical Trials, DM Finkelstein, DA Schoenfeld (eds).Google Scholar
  58. 58.
    Yusuf S, Collins R, Peto R (1984). Why do we need some large, simple trials? Stat Med 3:409–420.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1995

Authors and Affiliations

  • Dennis O. Dixon
  • Jeffrey M. Albert

There are no affiliations available

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