The Design of Randomized Controlled Trials

  • Bryan M. CurtisEmail author
  • Brendan J. Barrett
  • Patrick S. Parfrey
Part of the Methods in Molecular Biology™ book series (MIMB, volume 473)


Today's clinical practice relies on the application of well-designed clinical research, the gold standard test of an intervention being the randomized controlled trial. Principles of the randomized controlled trial include emphasis on the principal research question, randomization, and blinding; definitions of outcome measures, inclusion and exclusion criteria, and comorbid and confounding factors; enrolling an adequate sample size; planning data management and analysis; preventing challenges to trial integrity, such as dropout, drop-in, and bias. The application of pretrial planning is stressed to ensure the proper application of epidemiological principles, resulting in clinical studies that are feasible and generalizable. In addition, funding strategies and trial team composition are discussed

Key Words

Clinical trial randomization blinding sample size estimate 


  1. 1.
    1. Fuchs, F. D., Klag, M. J., Whelton, P. K. (2000) The classics: a tribute to the 50th anniversary of the randomized clinical trial. J Clin Epidemiol 53, 335–342.PubMedCrossRefGoogle Scholar
  2. 2.
    2. Whelton, P. K. (1994) Epidemiology of hypertension. Lancet 344, 101–106.PubMedCrossRefGoogle Scholar
  3. 3.
    3. Whelton, P. K., Gordis, L. (2000) Epidemiology of clinical medicine. Epidemiol Rev 22, 140–144.PubMedGoogle Scholar
  4. 4.
    4. Schulz, K. F., Grimes, D. A. (2002) Allocation concealment in randomised trials: Defending against deciphering. Lancet 359, 614–618.PubMedCrossRefGoogle Scholar
  5. 5.
    5. Yusuf, S., Sleight, P., Pogue, J., Bosch, J., Davies, R., Dagenais, G., The Heart Outcomes Prevention Evaluation Study Investigators. (2000) Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 342, 145–153.PubMedCrossRefGoogle Scholar
  6. 6.
    6. Yusuf, S., Dagenais, G., Pogue, J., Bosch, J., and Sleight, P., The Heart Outcomes Prevention Evaluation Study Investigators. (2000) Vitamin E supplementation and cardiovascular events in high-risk patients. N Engl J Med 342, 154–160.PubMedCrossRefGoogle Scholar
  7. 7.
    7. Scott, C. T., Baker, M. (2007) Overhauling clinical trials. Nat Biotechnol 25, 287–292.PubMedCrossRefGoogle Scholar
  8. 8.
    8. D'Agostino, R. B., Sr., Massaro, J. M., Sullivan, L. M. (2003) Non-inferiority trials: Design concepts and issues—the encounters of academic consultants in statistics. Stat Med 22, 169–186.PubMedCrossRefGoogle Scholar
  9. 9.
    9. Snapinn, S. M. (2000) Noninferiority trials. Curr Control Trials Cardiovasc Med 1, 19–21.PubMedCrossRefGoogle Scholar
  10. 10.
    10. Bakris, G. L., Whelton, P., Weir, M., Mimran, A., Keane, W., Schiffrin, E., Evaluation of Clinical Trial Endpoints in Chronic Renal Disease Study Group. (2000) The future of clinical trials in chronic renal disease: Outcome of an NIH/FDA/Physician Specialist Conference. J Clin Pharmacol 40, 815–825.PubMedCrossRefGoogle Scholar
  11. 11.
    11. Ponticelli, C., Zucchelli, P., Passerini, P., Cesana, B., Locatelli, F., Pasquali, S., Sasdelli, M., Redaelli, B., Grassi, C., Pozzi, C., et al. (1995) A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy. Kidney Int 48, 1600–1604.PubMedCrossRefGoogle Scholar
  12. 12.
    12. Whitehead, J. (2004) Stopping rules for clinical trials. Control Clin Trials 25, 69–70; author reply 71–72.PubMedCrossRefGoogle Scholar
  13. 13.
    13. Besarab, A., Bolton, W. K., Browne, J. K., Egrie, J. C., Nissenson, A. R., Okamoto, D. M., Schwab, S. J., Goodkin, D. A. (1998) The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 339, 584–590.PubMedCrossRefGoogle Scholar
  14. 14.
    14. Brenner, B. M., Cooper, M. E., de Zeeuw, D., Keane, W. F., Mitch, W. E., Parving, H. H., Remuzzi, G., Snapinn, S. M., Zhang, Z., Shahinfar, S. (2001) Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345, 861–869.PubMedCrossRefGoogle Scholar
  15. 15.
    15. Altman, D. G., Schulz, K. F., Moher, D., Egger, M., Davidoff, F., Elbourne, D., Gotzsche, P. C., Lang, T. (2001) The revised CONSORT statement for reporting randomized trials: Explanation and elaboration. Ann Intern Med 134, 663–694.PubMedGoogle Scholar
  16. 16.
    16. Plint, A. C., Moher, D., Morrison, A., Schulz, K., Altman, D. G., Hill, C., Gaboury, I. (2006) Does the CONSORT checklist improve the quality of reports of randomised controlled trials? A systematic review. Med J Aust 185, 263–267.PubMedGoogle Scholar

Copyright information

© Humana Press, a part of Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Bryan M. Curtis
    • 1
    Email author
  • Brendan J. Barrett
  • Patrick S. Parfrey
  1. 1.Health Sciences CentreNewfoundlandCanada

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