Skip to main content
SpringerLink
Log in

Basic Study Design

  • Chapter
Fundamentals of Clinical Trials

Abstract

The foundations for the design of controlled experiments were established for agricultural application. They are described in several classical statistics textbooks [1–4]. From these sources evolved the basic design of controlled clinical trials.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 89.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Fisher RA. Statistical Methods for Research Workers. Edinburgh: Oliver and Boyd, 1925.

    Google Scholar 

  2. Fisher RA. The Design of Experiments. Edinburgh: Oliver and Boyd, 1935.

    Google Scholar 

  3. Cochran WG, Cox GM Experimental Designs (2nd edition). New York: John Wiley and Sons, 1957.

    Google Scholar 

  4. Cox DR. Planning of Experiments. New York: John Wiley and Sons, 1958.

    Google Scholar 

  5. Bull JP. The historical development of clinical therapeutic trials. J Chronic Dis 1959;10:218–248.

    Article  Google Scholar 

  6. Eliot MM. The control of rickets: preliminary discussion of the demonstration in New Haven. JAMA 1925;85:656–663.

    Article  Google Scholar 

  7. Hill AB. Observation and experiment. N Engl J Med 1953;248:995–1001.

    Article  Google Scholar 

  8. Macfarlane G. Howard Florey: The Making of a Great Scientist. Oxford: Oxford University Press, 1979, pp11–12.

    Google Scholar 

  9. Gocke DJ. Fulminant hepatitis treated with serum containing antibody to Australia antigen. N Engl J Med 1971;284:919.

    Article  Google Scholar 

  10. Acute Hepatic Failure Study Group. Failure of specific immunotherapy in fulminant type B hepatitis. Ann Intern Med 1977;86:272–277.

    Article  Google Scholar 

  11. Snow JB Jr, Kimmelman CP. Assessment of surgical procedures for Ménière’s disease. Laryngoscope 1979;89:737–747.

    Article  Google Scholar 

  12. Armitage P, Berry G, Matthews JNS. Statistical Methods in Medical Research (4th edition). Malden, MA: Blackwell Publishing, 2002.

    Google Scholar 

  13. Brown BW, Hollander M. Statistics: A Biomedical Introduction. New York: John Wiley and Sons, 1977.

    Book  Google Scholar 

  14. Feinstein AR. Clinical Biostatistics. St Louis: The C.V. Mosby Company, 1977.

    Book  Google Scholar 

  15. MacMahon B, Trichopoulos D. Epidemiology: Principles and Methods (2nd edition). Lippincott Williams & Wilkins, 1996.

    Google Scholar 

  16. Lilienfeld DE, Stolley PD. Foundations of Epidemiology (3rd edition). New York: Oxford University Press, 1994.

    Google Scholar 

  17. Srivastava JN (ed.). A Survey of Statistical Design and Linear Models. Amsterdam: North-Hollard, 1975.

    Google Scholar 

  18. Peto R, Pike MC, Armitage P, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. 1. Introduction and design. Br J Cancer 1976;34:585–612.

    Article  Google Scholar 

  19. Brown BW Jr. Statistical controversies in the design of clinical trials—some personal views. Control Clin Trials 1980;1:13–27.

    Article  Google Scholar 

  20. Pocock SJ. Allocation of patients to treatment in clinical trials. Biometrics 1979;35:183–197.

    Article  Google Scholar 

  21. Brown BW Jr. The crossover experiment for clinical trials. Biometrics 1980;36:69–79.

    Article  Google Scholar 

  22. Hennekens CH, Buring JC. Epidemiology in Medicine. SL Mayrent (ed.). Boston: Little, Brown, 1987.

    Google Scholar 

  23. Byar DP. Some statistical considerations for design of cancer prevention trials. Prev Med 1989;18:688–699.

    Article  Google Scholar 

  24. Geller NL (ed.). Advances in Clinical Trial Biostatistics. New York: Marcel Dekker, 2003.

    Google Scholar 

  25. Piantadosi S. Clinical Trials: A Methodologic Perspective (2nd edition). New York: John Wiley and Sons, 2005.

    Google Scholar 

  26. Machin D, Day S, Green S. Textbook of Clinical Trials (2nd edition). West Sussex: John Wiley and Sons, 2006.

    Google Scholar 

  27. Green S, Benedetti J, Crowley J. Clinical Trials in Oncology (3rd edition). Boca Raton: CRC Press, 2012.

    Google Scholar 

  28. Hulley SB, Cummings SR, Browner WS, et al. Designing Clinical Research (4th edition). New York: Wolters Kluwer/Lippincott Williams & Wilkins, 2013.

    Google Scholar 

  29. Meinert CL. Clinical Trials: Design, Conduct, and Analysis (2nd edition). New York: Oxford University Press, 2012.

    Google Scholar 

  30. Cook TD, DeMets DL (eds). Introduction to Statistical Methods for Clinical Trials. Boca Raton: Chapman & Hall/CRC, Taylor & Francis Group, LLC, 2008.

    Google Scholar 

  31. Chow S-C, Shao J. Statistics in Drug Research: Methodologies and Recent Developments. New York: Marcel Dekker, 2002.

    Book  Google Scholar 

  32. Green SB, Byar DP. Using observational data from registries to compare treatments: the fallacy of omnimetrics. Stat Med 1984;3:361–373.

    Article  Google Scholar 

  33. Gehan EA, Freireich EJ. Non-randomized controls in cancer clinical trials. N Engl J Med 1974;290:198–203.

    Article  Google Scholar 

  34. Weinstein MC. Allocation of subjects in medical experiments. N Engl J Med 1974;291:1278–1285.

    Article  Google Scholar 

  35. Byar DP, Simon RM, Friedewald WT, et al. Randomized clinical trials: perspectives on some recent ideas. N Engl J Med 1976;295:74–80.

    Article  Google Scholar 

  36. Sapirstein W, Alpert S, Callahan TJ. The role of clinical trials in the Food and Drug Administration approval process for cardiovascular devices. Circulation 1994;89:1900–1902.

    Article  Google Scholar 

  37. Hlatky MA. Perspective: Evidence-based use of cardiac procedures and devices. N Engl J Med 2004;350:2126–2128.

    Article  Google Scholar 

  38. AMPLATZER® Septal Occluder. http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/Recently-ApprovedDevices/ucm083978.htm

  39. St. Jude Amplatzer Atrial Septal Occluder (ASO): Safety communication—reports of tissue erosion. http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm371202.htm

  40. Chalmers TC, Matta RJ, Smith H, Kunzier AM. Evidence favoring the use of anticoagulants in the hospital phase of acute myocardial infarction. N Engl J Med 1977;297:1091–1096.

    Article  Google Scholar 

  41. Peto R. Clinical trial methodology. Biomedicine (Special issue) 1978;28:24–36.

    Google Scholar 

  42. Goldman L, Feinstein AR. Anticoagulants and myocardial infarction: the problems of pooling, drowning, and floating. Ann Intern Med 1979;90:92–94.

    Article  Google Scholar 

  43. Grace ND, Muench H, Chalmers TC. The present status of shunts for portal hypertension in cirrhosis. Gastroenterology 1966;50:684–691.

    Article  Google Scholar 

  44. Sacks H, Chalmers TC, Smith H Jr. Randomized versus historical controls for clinical trials. Am J Med 1982;72:233–240.

    Article  Google Scholar 

  45. Sacks HS, Chalmers TC, Smith H Jr. Sensitivity and specificity of clinical trials: randomized v historical controls. Arch Intern Med 1983;143:753–755.

    Article  Google Scholar 

  46. Chalmers TC, Celano P, Sacks HS, Smith H Jr. Bias in treatment assignment in controlled clinical trials. N Engl J Med 1983;309:1358–1361.

    Article  Google Scholar 

  47. Ingelfinger FJ. The randomized clinical trial (editorial). N Engl J Med 1972;287:100–101.

    Article  Google Scholar 

  48. Zelen M. A new design for randomized clinical trials. N Engl J Med 1979;300:1242–1245.

    Article  Google Scholar 

  49. Anbar D. The relative efficiency of Zelen’s prerandomization design for clinical trials. Biometrics 1983;39:711–718.

    Article  Google Scholar 

  50. Ellenberg SS. Randomization designs in comparative clinical trials. N Engl J Med 1984;310:1404–1408.

    Article  Google Scholar 

  51. Zelen M. Randomized consent designs for clinical trials: an update. Stat Med 1990;9:645–656.

    Article  Google Scholar 

  52. Gehan EA. The evaluation of therapies: historical control studies. Stat Med 1984;3:315–324.

    Article  Google Scholar 

  53. Lasagna L. Historical controls: the practitioner’s clinical trials. N Engl J Med 1982;307:1339–1340.

    Article  Google Scholar 

  54. Moertel CG. Improving the efficiency of clinical trials: a medical perspective. Stat Med 1984;3:455–465.

    Article  Google Scholar 

  55. Pocock SJ. Letter to the editor. Br Med J 1977;1:1661.

    Article  Google Scholar 

  56. Veterans Administration Cooperative Urological Research Group. Treatment and survival of patients with cancer of the prostate. Surg Gynecol Obstet 1967;124:1011–1017.

    Google Scholar 

  57. Packer M, O’Connor CM, Ghali JK, et al. for the Prospective Randomized Amlodipine Survival Evaluation Study Group. Effect of amlodipine on morbidity and mortality in severe chronic heart failure. N Engl J Med 1996;335:1107–1114.

    Google Scholar 

  58. Packer M, Carson P, Elkayam U, et al. Effect of amlodipine on the survival of patients with severe chronic heart failure due to a nonischemic cardiomyopathy. JACC:Heart Failure 2013;1:308–314.

    Google Scholar 

  59. Havlik RJ, Feinleib M (eds.). Proceedings of the Conference on the Decline in Coronary Heart Disease Mortality. Washington, D.C.: NIH Publication No. 79-1610, 1979.

    Google Scholar 

  60. Health, United States, 2011, With Special Feature on Socioeconomic Status and Health. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics. http://www.cdc.gov/nchs/data/hus/hus11.pdf, page 32, figure 3.

  61. Health, United States, 2008, With Special Feature on the Health of Young Adults. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics. http://www.cdc.gov/nchs/data/hus/hus08.pdf, page 37, figure 9.

  62. Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart disease. JAMA 1975;231:360–381.

    Article  Google Scholar 

  63. Castro KG, Ward JW, Slutsker L, et al. 1993 revised classification system for HIV infection and expanded surveillance case definitions for AIDS among adolescents and adults. MMWR Recomm Rep, December 18, 1992.

    Google Scholar 

  64. Current trends update: trends in AIDS diagnosis and reporting under the expanded surveillance definition for adolescents and adults—United States, 1993. MMWR Weekly 1994;43:826–831.

    Google Scholar 

  65. Rosenberg HM, Klebba AJ. Trends in cardiovascular mortality with a focus on ischemic heart disease: United States, 1950-1976. In Havlik R, Feinleib M (eds). Proceedings of the Conference on the Decline in Coronary Heart Disease Mortality. Washington, D.C.: NIH Publication No. 79-1610, 1979.

    Google Scholar 

  66. Morbidity and Mortality Chartbook on Cardiovascular, Lung, and Blood Diseases. National Heart, Lung, and Blood Institute, U.S. Department of Health and Human Services, Public Health Service. May 1994.

    Google Scholar 

  67. Centers for Disease Control and Prevention. International Classification of Diseases, (ICD-10-CN/PCS) Transition. http://www.cdc.gov/nchs/icd/icd10cm_pcs_impact.htm

  68. Bailar JC III, Louis TA, Lavori PW, Polansky M. Studies without internal controls. N Engl J Med 1984;311:156–162.

    Article  Google Scholar 

  69. Dustan HP, Schneckloth RE, Corcoran AC, Page IH. The effectiveness of long-term treatment of malignant hypertension. Circulation 1958;18:644–651.

    Article  Google Scholar 

  70. Bjork S, Sannerstedt R, Angervall G, Hood B. Treatment and prognosis in malignant hypertension: clinical follow-up study of 93 patients on modern medical treatment. Acta Med Scand 1960;166:175–187.

    Article  Google Scholar 

  71. Bjork S, Sannerstedt R, Falkheden T, Hood B. The effect of active drug treatment in severe hypertensive disease: an analysis of survival rates in 381 cases on combined treatment with various hypotensive agents. Acta Med Scand 1961;169:673–689.

    Article  Google Scholar 

  72. Starmer CF, Lee KL, Harrell FE, Rosati RA. On the complexity of investigating chronic illness. Biometrics 1980;36:333–335.

    Article  Google Scholar 

  73. Hlatky MA, Lee KL, Harrell FE Jr, et al. Tying clinical research to patient care by use of an observational database. Stat Med 1984;3:375–387.

    Article  Google Scholar 

  74. Hlatky MA, Califf RM, Harrell FE Jr, et al. Clinical judgment and therapeutic decision making. J Am Coll Cardiol 1990;15:1–14.

    Article  Google Scholar 

  75. Moon TE, Jones SE, Bonadonna G, et al. Using a database of protocol studies to evaluate therapy: a breast cancer example. Stat Med 1984;3:333–339.

    Article  Google Scholar 

  76. Anderson C. Measuring what works in health care. Science 1994;263:1080–1082.

    Article  Google Scholar 

  77. Klungel OH, Heckbert SR, Longstreth WT, et al. Antihypertensive drug therapies and the risk of ischemic stroke. Arch Intern Med 2001;161:37–43.

    Article  Google Scholar 

  78. Graham DJ, Campen D, Hui R, et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet 2005;365:475–481.

    Article  Google Scholar 

  79. Byar, DP. Why databases should not replace randomized clinical trials. Biometrics 1980;36:337–342.

    Article  Google Scholar 

  80. Dambrosia JM, Ellenberg JH. Statistical considerations for a medical database. Biometrics 1980;36:323–332.

    Article  Google Scholar 

  81. Sheldon TA. Please bypass the PORT. Br Med J 1994;309:142–143.

    Article  Google Scholar 

  82. Mantel N. Cautions on the use of medical databases. Stat Med 1983;2:355–362.

    Article  Google Scholar 

  83. Lauer MS, D’Agostino RB, Sr. The randomized registry trial—the next disruptive technology in clinical research? N Engl J Med 2013;369:1579–1581.

    Article  Google Scholar 

  84. Frӧbert O, Lagerqvist B, Olivecrona GK, et al. Thrombus aspiration during ST-elevation myocardial infarction. N Engl J Med 2013:369:1587–1597; correction. N Engl J Med 2014;371:786.

    Google Scholar 

  85. Carriere KC. Crossover designs for clinical trials. Stat Med 1994;13:1063–1069.

    Article  Google Scholar 

  86. Koch GG, Amara IA, Brown BW Jr, et al. A two-period crossover design for the comparison of two active treatments and placebo. Stat Med 1989;8:487–504.

    Article  Google Scholar 

  87. Fleiss JL. A critique of recent research on the two treatment crossover design. Control Clin Trials 1989;10:237–243.

    Article  Google Scholar 

  88. Woods JR, Williams JG, Tavel M. The two-period crossover design in medical research. Ann Intern Med 1989;110:560–566.

    Article  Google Scholar 

  89. Louis TA, Lavori PW, Bailar JC III, Polansky M. Crossover and self-controlled designs in clinical research. N Engl J Med 1984;310:24–31.

    Article  Google Scholar 

  90. James KE, Forrest WH, Jr, Rose RL. Crossover and noncrossover designs in four-point parallel line analgesic assays. Clin Pharmacol Ther 1985;37:242–252.

    Article  Google Scholar 

  91. Mills EJ, Chan A-W, Wu P, et al. Design, analysis, and presentation of crossover trials. Trials 2009;10:27 doi:10.1186/1745-6215-10-27.

    Article  Google Scholar 

  92. International Conference on Harmonisation: E9 Statistical principles for clinical trials. http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129505.pdf.

  93. Grizzle JE. The two period change-over design and its use in clinical trials. Biometrics 1965;21:467–480.

    Article  Google Scholar 

  94. Fleiss JL, Wallenstein S, Rosenfeld R. Adjusting for baseline measurements in the two-period crossover study: a cautionary note. Control Clin Trials 1985;6:192–197.

    Article  Google Scholar 

  95. Hills M, Armitage P. The two-period cross-over clinical trial. Br J Clin Pharmacol 1979;8:7–20.

    Article  Google Scholar 

  96. Hypertension Detection and Follow-up Program Cooperative Group. Five-year findings of the Hypertension Detection and Follow-Up Program. 1. Reduction in mortality of persons with high blood pressure, including mild hypertension. JAMA 1979;242:2562–2571.

    Google Scholar 

  97. Stamler R, Stamler J, Grimm R, et al. Nutritional therapy for high blood pressure-Final report of a four-year randomized controlled trial—The Hypertension Control Program. JAMA 1987;257:1484–1491.

    Article  Google Scholar 

  98. Magnussen H, Disse B, Rodriguez-Roisin R, et al. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med 2014;371:1285–1294.

    Article  Google Scholar 

  99. Report of the Sixty Plus Reinfarction Study Research Group. A double-blind trial to assess long-term oral anticoagulant therapy in elderly patients after myocardial infarction. Lancet 1980;316:989–994.

    Article  Google Scholar 

  100. Kasiske BL, Chakkera HA, Louis TA, Ma JZ. A meta-analysis of immunosuppression withdrawal trials in renal transplantation. J Am Soc Nephrol 2000;11:1910–1917.

    Article  Google Scholar 

  101. Black DM, Schwartz AV, Ensrud KE, et al, for the FLEX Research Group. Effects of continuing or stopping alendronate after 5 years of treatment: The Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA 2006;296:2927–2938.

    Google Scholar 

  102. Montgomery AA, Peters TJ, Little P. Design, analysis and presentation of factorial randomized controlled trials. BMC Med Res Methodol 2003;3:26doi:10.1186/1471-2288-3-26.

  103. The Canadian Cooperative Study Group. A randomized trial of aspirin and sulfinpyrazone in threatened stroke. N Engl J Med 1978;299:53–59.

    Article  Google Scholar 

  104. ISIS-3 (Third International Study of Infarct Survival) Collaborative Group. ISIS-3: a randomized study of streptokinase vs plasminogen activator vs anistrephase and of aspirin plus heparin vs aspirin alone among 41,299 cases of suspected acute myocardial infarction. Lancet 1992;339:753–770.

    Google Scholar 

  105. Stampfer MJ, Buring JE, Willett W, et al. The 2 x 2 factorial design: its application to a randomized trial of aspirin and carotene in U.S. physicians. Stat Med 1985;4:111–116.

    Article  Google Scholar 

  106. Design of the Women’s Health Initiative clinical trial and observational study. The Women’s Health Initiative Study Group. Control Clin Trials 1998;19:61–109.

    Article  Google Scholar 

  107. McAlister FA, Straus SE, Sackett DL, Altman DG. Analysis and reporting of factorial trials: a systematic review. JAMA 2003;289:2545–2553.

    Article  Google Scholar 

  108. Byar DP, Herzberg AM, Tan W-Y. Incomplete factorial designs for randomized clinical trials. Stat Med 1993;12:1629–1641.

    Article  Google Scholar 

  109. Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in Type 2 diabetes. N Engl J Med 2008;358:2545–2559.

    Article  Google Scholar 

  110. Fletcher DJ, Lewis SM, Matthews JNS. Factorial designs for crossover clinical trials. Stat Med 1990;9:1121–1129.

    Article  Google Scholar 

  111. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321–333.

    Article  Google Scholar 

  112. The Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. JAMA 2004;291:1701–1712.

    Article  Google Scholar 

  113. Brittain E, Wittes J. Factorial designs in clinical trials: the effects of non-compliance and subadditivity. Stat Med 1989;8:161–171.

    Article  Google Scholar 

  114. Hayes RJ, Moulton LH. Cluster Randomized Trials: A Practical Approach. Chapman & Hall/CRC, Taylor & Francis Group, 2009.

    Google Scholar 

  115. Donner A, Birkett N, Buck C. Randomization by cluster: sample size requirements and analysis. Am J Epidemiol 1981;114:906–914.

    Article  Google Scholar 

  116. Armitage P. The role of randomization in clinical trials. Stat Med 1982;1:345–352.

    Article  Google Scholar 

  117. Simon R. Composite randomization designs for clinical trials. Biometrics 1981;37:723–731.

    Article  Google Scholar 

  118. Cornfield J. Randomization by group: a formal analysis. Am J Epidemiol 1978;108:100–102.

    Article  Google Scholar 

  119. Zucker DM, Lakatos E, Webber LS, et al. Statistical design of the Child and Adolescent Trial for Cardiovascular Health (CATCH): implications of cluster randomization. Control Clin Trials 1995;16:96–118.

    Article  Google Scholar 

  120. Vijayaraghavan K, Radhaiah G, Prakasam BS, et al. Effect of massive dose vitamin A on morbidity and mortality in Indian children. Lancet 1990;336:1342–1345.

    Article  Google Scholar 

  121. Luepker RV, Raczynski JM, Osganian S, et al. Effect of a community intervention on patient delay and emergency medical service use in acute coronary heart disease: the Rapid Early Action for Coronary Treatment (REACT) trial. JAMA 2000;284:60–67.

    Article  Google Scholar 

  122. Farquhar JW, Fortmann SP, Flora JA, et al. Effects of community-wide education on cardiovascular disease risk factors. The Stanford Five-City Project. JAMA 1990;264:359–365.

    Google Scholar 

  123. Gail MH, Byar DP, Pechacek TF, Corle DK, for COMMIT Study Group. Aspects of statistical design for the Community Intervention Trial for Smoking Cessation. Control Clin Trials 1992;13:6–21.

    Google Scholar 

  124. Sismanidis C, Moulton LH, Ayles H, et al. Restricted randomization of ZAMSTAR: a 2x2 factorial cluster randomized trial. Clin Trials 2008;5:316–327.

    Article  Google Scholar 

  125. Hussey MA, Hughes JP. Design and analysis of stepped wedge cluster randomized trials. Contemp Clin Trials 2007;28:182–191.

    Article  Google Scholar 

  126. Woertman W, de Hoop E, Moerbeek M, et al. Stepped wedge designs could reduce the required sample size in cluster randomized trials. J Clin Epidemiol 2013;66:752–758.

    Article  Google Scholar 

  127. Pocock SJ. The combination of randomized and historical controls in clinical trials. J Chronic Dis 1976;29:175–188.

    Article  Google Scholar 

  128. Machin D. On the possibility of incorporating patients from nonrandomising centres into a randomised clinical trial. J Chronic Dis 1979;32:347–353.

    Article  Google Scholar 

  129. Gruppo Italiano per lo Studio della Streptochinasi nell’ Infarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986;i:397–402.

    Google Scholar 

  130. The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329:673–682; correction N Engl J Med 1994;331:277.

    Google Scholar 

  131. The Digitalis Investigation Group. Rationale, design, implementation, and baseline characteristics of patients in the DIG Trial: a large, simple, long-term trial to evaluate the effect of digitalis on mortality in heart failure. Control Clin Trials 1996;17:77–97.

    Article  Google Scholar 

  132. MICHELANGELO OASIS 5 Steering Committee. Design and rationale of the MICHELANGELO Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS)-5 trial program evaluating fondaparinux, a synthetic factor Xa inhibitor, in patients with non-ST-segment elevation acute coronary syndromes. Am Heart J 2005;150:1107–1114.

    Google Scholar 

  133. Tunis SR, Stryer DB, Clancy CM. Practical clinical trials: increasing the value of clinical research for decision making in clinical and health policy. JAMA 2003;290:1624–1632.

    Article  Google Scholar 

  134. March JS, Silva SG, Compton S, et al. The case for practical clinical trials in psychiatry. Am J Psychiatry 2005;162:836–846.

    Article  Google Scholar 

  135. Thorpe KE, Zwarenstein M, Oxman AD, et al. A pragmatic-explanatory continuum indicator summary (PRECIS): a tool to help trial designers. J Clin Epidemiol 2009;62:464–475.

    Article  Google Scholar 

  136. Johnson KE, Tachibana C, Coronado GD, et al. Research Methods & Reporting: A guide to research partnerships for pragmatic trials. BMJ 2014;349:g6826 doi:10.1136/bmj.g6826.

    Article  Google Scholar 

  137. Mailankody S, Prasad V. Perspective: Comparative effectiveness questions in oncology. N Engl J Med 2014; 370:1478–1481.

    Article  Google Scholar 

  138. Ross JS, Slodkowska EA, Symmans WF, et al. The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist 2009;14:320–368.

    Article  Google Scholar 

  139. Lai TL, Lavori PW, Shih MC, Sikic BI. Clinical trial designs for testing biomarker-based personalized therapies. Clin Trials 2012;9:141–154.

    Article  Google Scholar 

  140. The CATT Research Group. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 2011;364:1897–1908.

    Article  Google Scholar 

  141. Blackwelder WC. “Proving the null hypothesis” in clinical trials. Control Clin Trials 1982;3:345–353.

    Article  Google Scholar 

  142. Hung JHM, Wang SJ, Tsong Y, et al. Some fundamental issues with non-inferiority testing in active controlled trials. Stat Med 2003;30:213–225.

    Article  Google Scholar 

  143. Fleming TR. Current issues in non-inferiority trials. Stat Med 2008;27:317–332.

    Article  MathSciNet  Google Scholar 

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

    Article  Google Scholar 

  145. Kaul S, Diamond GA. Making sense of noninferiority: a clinical and statistical perspective on its application to cardiovascular clinical trials. Prog Cardiovasc Dis 2007;49:284–299.

    Article  Google Scholar 

  146. Mulla SM, Scott IA, Jackevicius CA, You JJ, Guyatt GH. How to use a noninferiority trial. JAMA 2012;308:2605–2611.

    Article  Google Scholar 

  147. Schumi J, Wittes JT. Through the looking glass: understanding non-inferiority. Trials 2011;12:106 doi:10.1186/1745-6215-12-106.

    Article  Google Scholar 

  148. DeMets DL, Friedman L. Some thoughts on challenges for noninferiority study designs. Therapeutic Innovation & Regulatory Science 2012;46:420–427.

    Google Scholar 

  149. SPORTIF Executive Steering Committee for the SPORTIF V Investigators. Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial. JAMA 2005;293:690–698.

    Article  Google Scholar 

  150. Trivedi MH, Rush AJ, Wisniewski SR, et al, for the STAR*D Study Team. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 2006;163:28–40.

    Article  Google Scholar 

  151. Murphy SA, Oslin DW, Rush AJ, Zhu J, for MCATS. Methodological challenges in constructing effective treatment sequences for chronic psychiatric disorders (Perspective). Neuropsychopharmacology 2007;32:257–262.

    Google Scholar 

  152. Lavori PW, Dawson D. Improving the efficiency of estimation in randomized trials of adaptive treatment strategies. Clin Trials 2007;4:297–308.

    Article  Google Scholar 

  153. Levin GP, Emerson SC, Emerson SS. Adaptive clinical trial designs with prespecified rules for modifying the sample size: understanding efficient types of adaptation. Stat Med 2013;32:1259–1275.

    Article  MathSciNet  Google Scholar 

  154. Mehta C. Adaptive clinical trial designs with pre-specified rules for modifying the sample size: a different perspective. Stat Med 2013;32:1276–1279.

    Article  MathSciNet  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. North Bethesda, MD, USA

    Lawrence M. Friedman

  2. Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA

    Curt D. Furberg

  3. Department Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI, USA

    David L. DeMets

  4. Department of Biostatistics, Wake Forest School of Medicine, Winston-Salem, NC, USA

    David M. Reboussin

  5. Department of Medicine, Duke University, Durham, NC, USA

    Christopher B. Granger

Authors
  1. Lawrence M. Friedman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Curt D. Furberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David L. DeMets
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David M. Reboussin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christopher B. Granger
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Friedman, L.M., Furberg, C.D., DeMets, D.L., Reboussin, D.M., Granger, C.B. (2015). Basic Study Design. In: Fundamentals of Clinical Trials. Springer, Cham. https://doi.org/10.1007/978-3-319-18539-2_5

Download citation

Publish with us

Policies and ethics

Search

Navigation