Skip to main content
SpringerLink
Log in

Introduction to Clinical Trials

  • Chapter
Fundamentals of Clinical Trials

Abstract

The evolution of the modern clinical trial dates back at least to the eighteenth century [1, 2]. Lind, in his classical study on board the Salisbury, evaluated six treatments for scurvy in 12 patients. One of the two who was given oranges and lemons recovered quickly and was fit for duty after 6 days. The second was the best recovered of the others and was assigned the role of nurse to the remaining ten patients. Several other comparative studies were also conducted in the eighteenth and nineteenth centuries. The comparison groups comprised literature controls, other historical controls, and concurrent controls [2].

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

Similar content being viewed by others

References

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

    Google Scholar 

  2. Lilienfeld AM. Ceteris paribus: the evolution of the clinical trial. Bull Hist Med 1982;56:1–18.

    Google Scholar 

  3. Box JF. R. A. Fisher and the design of experiments, 1922–1926. Am Stat 1980;34:1–7.

    MathSciNet  Google Scholar 

  4. Amberson JB, Jr, McMahon BT, Pinner M. A clinical trial of sanocrysin in pulmonary tuberculosis. Am Rev Tuberc 1931;24:401–435.

    Google Scholar 

  5. Medical Research Council. Streptomycin treatment of pulmonary tuberculosis. Br Med J 1948;2:769–782.

    Google Scholar 

  6. Hart PD. Letter to the Editor:Randomised controlled clinical trials. Br Med J 1991;302:1271–1272.

    Article  Google Scholar 

  7. Diehl HS, Baker AB, Cowan DW Cold vaccines; an evaluation based on a controlled study. JAMA 1938;111:1168–1173.

    Article  Google Scholar 

  8. Freireich EJ, Frei E, III, Holland JF, et al. Evaluation of a new chemotherapeutic agent in patients with “advanced refractory” acute leukemia: studies of 6–azauracil. Blood 1960;16:1268–1278.

    Article  Google Scholar 

  9. Hill AB. The clinical trial. Br Med Bull 1951;7:278–282.

    Article  Google Scholar 

  10. Hill AB. The clinical trial. N Engl J Med 1952;247:113–119.

    Article  Google Scholar 

  11. Hill AB. Statistical Methods of Clinical and Preventive Medicine. 1962; Oxford University Press, New York.

    Google Scholar 

  12. Doll R. Clinical trials: Retrospect and prospect. Stat Med 1982;1:337–344.

    Article  Google Scholar 

  13. Chalmers I. Comparing like with like: some historical milestones in the evolution of methods to create unbiased comparison groups in therapeutic experiments. Int J Epidemiol 2001;30:1156–1164.

    Article  Google Scholar 

  14. Gehan EA, Schneiderman MA. Historical and methodological developments in clinical trials at the National Cancer Institute. Stat Med 1990;9:871–880.

    Article  Google Scholar 

  15. Halperin M, DeMets DL, Ware JH. Early methodological developments for clinical trials at the National Heart, Lung, and Blood Institute. Stat Med 1990;9:881–892.

    Article  Google Scholar 

  16. Greenhouse SW. Some historical and methodological developments in early clinical trials at the National Institutes of Health. Stat Med 1990;9:893–901.

    Article  Google Scholar 

  17. Byar DP. Discussion of papers on "historical and methodological developments in clinical trials at the National Institutes of Health." Stat Med 1990; 9:903–906.

    Article  Google Scholar 

  18. Organization, review, and administration of cooperative studies (Greenberg Report): A report from the Heart Special Project Committee to the National Advisory Heart Council, May 1967. Control Clin Trials 1988; 9:137–148.

    Google Scholar 

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

    Article  Google Scholar 

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

    Article  Google Scholar 

  21. OPRR Reports. Code of Federal Regulations: (45 CFR 46) Protection of Human Subjects. National Institutes of Health, Department of Health and Human Services. Revised January 15, 2009. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html

  22. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report: ethical principles and guidelines for the protection of human subjects of research. Federal Register 1979;44:23192-23197. http://archive.hhs.gov/ohrp/humansubjects/guidance/belmont.htm

  23. Nuremburg Code. http://www.hhs.gov/ohrp/archive/nurcode.html

  24. World Medical Association Declaration of Helsinki. http://www.wma.net/en/30publications/10policies/b3/index.html

  25. Chan A-W, Tetzlaff JM, Altman DG, et al. SPIRIT 2013 Statement: defining standard protocol items for clinical trials. Ann Intern Med 2013;158:200–207.

    Article  Google Scholar 

  26. International Harmonised Tripartite Guideline: General Considerations for Clinical Trials: E8. July 17, 1997. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E8/Step4/E8_Guideline.pdf.

  27. Buoen C, Bjerrum OJ, Thomsen MS. How first-time-in-human studies are being performed: a survey of phase 1 dose-escalation trials in healthy volunteers published between 1995 and 2004. J Clin Pharmacol 2005;45:1123–1136.

    Article  Google Scholar 

  28. Carbone PP, Krant MJ, Miller SP, et al. The feasibility of using randomization schemes early in the clinical trials of new chemotherapeutic agents:hydroxyurea (NSC-32065). Clin Pharmacol Ther 1965;6:17–24.

    Article  Google Scholar 

  29. Anbar D. Stochastic approximation methods and their use in bioassay and Phase I clinical trials. Comm Stat Series A. 1984;13:2451–2467.

    Google Scholar 

  30. Williams DA. Interval estimation of the median lethal dose. Biometrics 1986;42:641-645; correction in: Biometrics 1987;43:1035.

    Google Scholar 

  31. Storer B, DeMets D. Current phase I/II designs: are they adequate? J Clin Res Drug Devel 1987;1:121–130.

    Google Scholar 

  32. Storer B. Design and analysis of phase I clinical trials. Biometrics 1989;45:925–937.

    Article  MathSciNet  Google Scholar 

  33. Gordon NH, Willson JK. Using toxicity grades in the design and analysis of cancer phase I clinical trials. Stat Med 1992;11:2063–2075.

    Article  Google Scholar 

  34. Schneiderman MA. Mouse to man: statistical problems in bringing a drug to clinical trial. Proceedings of the 5th Berkeley Symposium of Math and Statistical Problems, University of California 1967;4:855–866.

    Google Scholar 

  35. O'Quigley J, Pepe M, Fisher L. Continual reassessment method: a practical design for Phase I clinical trials in cancer. Biometrics 1990;46:33–48.

    Article  MathSciNet  Google Scholar 

  36. O'Quigley J, Chevret S. Methods for dose finding studies in cancer clinical trials: a review and results of a Monte Carlo Study. Stat Med 1991;10:1647–1664.

    Article  Google Scholar 

  37. Wang O, Faries DE. A two-stage dose selection strategy in phase 1 trials with wide dose ranges. J Biopharm Stat 2000;10:319–333.

    Article  Google Scholar 

  38. Babb J, Rogatko A. Bayesian methods for cancer phase I clinical trials. In: N. Geller (Ed.), Advances in Clinical Trial Biostatistics. New York: Marcel Dekker, 2004, pages 1–39.

    Google Scholar 

  39. Biswas S, Liu DD, Lee JJ, Berry DA. Bayesian clinical trials at the University of Texas M. D. Anderson Cancer Center. Clin Trials 2009;6:205–216.

    Article  Google Scholar 

  40. Garrett-Mayer E. The continual reassessment method for dose-finding studies: a tutorial. Clin Trials 2006;3:57–71.

    Article  Google Scholar 

  41. Babb J, Rogatko A, Zacks S. Cancer phase I clinical trials: efficient dose escalation with overdose control. Stat Med 1998;17:1103–1120.

    Article  Google Scholar 

  42. Thall PF, Millikan RE, Mueller P, Lee S-J. Dose-finding with two agents in phase I oncology trials. Biometrics 2003;59:487–496.

    Article  MathSciNet  Google Scholar 

  43. Cheung Y K, Chappell R. Sequential designs for phase I clinical trials with late-onset toxicities. Biometrics 2000;56:1177–1182.

    Article  MathSciNet  Google Scholar 

  44. Crowley J, Hoering A (eds.) Handbook of Statistics in Clinical Oncology (third edition). Boca Raton, FL: Chapman and Hall/CRC, 2012.

    Google Scholar 

  45. Ting N (ed.) Dose Finding in Drug Development. New York: Springer, 2006.

    Google Scholar 

  46. Gehan EA. The determination of the number of patients required in a follow-up trial of a new chemotherapeutic agent. J Chron Dis 1961;13:346–353.

    Article  Google Scholar 

  47. Fleming TR. One-sample multiple testing procedures for phase II clinical trials. Biometrics 1982;38:143–151.

    Article  Google Scholar 

  48. Herson J. Predictive probability early termination plans for phase II clinical trials. Biometrics 1979;35:775–783.

    Article  Google Scholar 

  49. Geller NL. Design of Phase I and II clinical trials in cancer: a statistician's view. Cancer Invest 1984;2:483–491.

    Article  Google Scholar 

  50. Whitehead J. Sample sizes for Phase II and Phase III clinical trials: an integrated approach. Stat Med 1986;5:459–464.

    Article  Google Scholar 

  51. Chang MN, Therneau TM, Wieand HS, Cha SS. Designs for group sequential phase II clinical trials. Biometrics 1987;43:865–874.

    Article  Google Scholar 

  52. Simon R, Wittes RE, Ellenberg SS. Randomized phase II clinical trials. Cancer Treat Rep 1985;69:1375–1381.

    Google Scholar 

  53. Jung S, Carey M, Kim K. Graphical search for two-stage designs for phase II clinical trials. Control Clin Trials 2001;22:367–372.

    Article  Google Scholar 

  54. Case LD, Morgan TM. Duration of accrual and follow-up for two-stage clinical trials. Lifetime Data Anal 2001;7:21–37.

    Article  MathSciNet  Google Scholar 

  55. Thall P, Simon R. Recent developments in the design of phase II clinical trials. In: Recent Advances in Clinical Trial Design and Analysis. P. Thall, (Ed.). New York: Springer Science+Business Media 1995, pages 49–72.

    Google Scholar 

  56. Grieve AP, Krams M. ASTIN: a Bayesian adaptive dose-response trial in acute stroke. ClinTrials 2005;2:340–351.

    Google Scholar 

  57. Lee YJ, Staquet M, Simon R, et al. Two-stage plans for patient accrual in phase II cancer clinical trials. Cancer Treat Rep 1979;63:1721–1726.

    Google Scholar 

  58. Schaid DJ, Ingle JN, Wieand S, Ahmann DL. A design for phase II testing of anticancer agents within a phase III clinical trial. Control Clin Trials 1988;9:107–118.

    Article  Google Scholar 

  59. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989;10:1–10.

    Article  Google Scholar 

  60. Thall PF, Simon R. Incorporating historical control data in planning phase II clinical trials. Stat Med 1990;9:215–228.

    Article  Google Scholar 

  61. Schmidli H, Bretz F, Racine-Poon A. Bayesian predictive power for interim adaptation in seamless phase II/III trials where the endpoint is survival up to some specified timepoint Stat Med 2007;26:4925–4938.

    Article  MathSciNet  Google Scholar 

  62. Sylvester RJ, Staquet MJ. Design of phase II clinical trials in cancer using decision theory. Cancer Treat Rep 1980;64:519–524.

    Google Scholar 

  63. Berry D. Decision analysis and Bayesian methods in clinical trials. In: Recent Advances in Clinical Trial Design and Analysis. P Thall (Ed.). New York: Springer Science+Business Media, 1995, pages 125-154.

    Chapter  Google Scholar 

  64. Laparoscopic Uterine Power Morcellation in Hysterectomy and Myomectomy: FDA Safety Communication. http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm393576.htm.

  65. Solomon SD, McMurray JJV, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005;352:1071–1080.

    Article  Google Scholar 

  66. Psaty BM, Furberg CD. COX-2 inhibitors—lessons in drug safety. N Engl J Med 2005;352:1133–1135.

    Google Scholar 

  67. Bolen S, Feldman L, Vassy J, et al. Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med 2007;147:386–399.

    Article  Google Scholar 

  68. Tricoci PL, Allen JM, Kramer JM, Califf RM, Smith SC Jr. Scientific evidence underlying the ACC/AHA clinical practice guidelines. JAMA 2009;301:831-841; erratum in JAMA 2009;301:1544.69.

    Google Scholar 

  69. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353:1673–1684.

    Article  Google Scholar 

  70. Piccart-Gebhart MJ, Proctor M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353:1659–1672.

    Article  Google Scholar 

  71. Smith I, Proctor M, Gelber RD, et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 2007;369:29–36.

    Article  Google Scholar 

  72. Kimmel SE, French B, Kasner, et al. A pharmacogenetic versus a clinical algorithm for warfarin dosing. N Engl J Med 2013;369:2283–2293.

    Article  Google Scholar 

  73. Verhoef TI, Ragia G, de Boer A, et al. A randomized trial of genotype-dosing of acenocoumarol and phenprocoumon. N Engl J Med 2013;369:2304–2312.

    Article  Google Scholar 

  74. Pirmohamed M, Burnside G, Eriksson N, et al. A randomized trial of genotype-guided dosing of warfarin. N Engl J Med 2013;369:2294–2303.

    Article  Google Scholar 

  75. Zineh I, Pacanowski M, Woodcock J. Pharmacogenetics and coumarin dosing—recalibrating expectations. N Engl J Med 2013;369:2273–2275.

    Article  Google Scholar 

  76. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997;336:525–533.

    Article  Google Scholar 

  77. The Intermittent Positive Pressure Breathing Trial Group. Intermittent positive pressure breathing therapy of chronic obstructive pulmonary disease-a clinical trial. Ann Intern Med 1983;99:612–620.

    Article  Google Scholar 

  78. Silverman WA. The lesson of retrolental fibroplasia. Sci Am 1977;236:100–107.

    Article  Google Scholar 

  79. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991;324:781–788.

    Article  Google Scholar 

  80. Alderson P, Roberts I. Corticosteroids for acute traumatic brain injury. Cochrane Database SystRev 2000;(2):CD000196.

    Google Scholar 

  81. Roberts I, Yates D, Sandercock P, et al. Effect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): randomised placebo-controlled trial. Lancet 2004;364:1321–1328.

    Article  Google Scholar 

  82. Edwards P, Arango M, Balica L, et al. Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury—outcomes at 6 months. Lancet 2005;365:1957–1959.

    Article  Google Scholar 

  83. Alderson P, Roberts I. Corticosteroids for acute traumatic brain injury. Cochrane Summaries 2009; (http://summaries.cochrane.org/CD000196/INJ_corticosteroids-to-treat-brain-injury.

  84. Stone NJ, Robinson J, Lichtenstein AH, et al.ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2889-2934; erratum in J Am Coll Cardiol 2014;63:3024–3025.

    Google Scholar 

  85. Canner PL, Furberg CD, McGovern ME. Benefits of niacin in patients with versus without the metabolic syndrome and healed myocardial infarction (from the Coronary Drug Project). Am J Cardiol 2006;97:477–479.

    Article  Google Scholar 

  86. The AIM-HIGH Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365:2255–2267.

    Article  Google Scholar 

  87. The HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014; 371:203–212.

    Article  Google Scholar 

  88. Stone GW, Lansky AJ, Pocock SJ, et al. Paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction. N Engl J Med 2009;360:1946–1959.

    Article  Google Scholar 

  89. James SK, Stenestrand U, Lindbäck J, et al. Long-term safety and efficacy of drug-eluting versus bare-metal stents in Sweden. N Engl J Med 2009;360:1933–1945.

    Article  Google Scholar 

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

    Article  Google Scholar 

  91. IVAN Study Investigators. Chakravarthy U, Harding SP, Rogers CA, et al. Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial. Ophthalmology 2012;119:1399-1411; erratum in Ophthalmology 2012;119:1508 and Ophthalmology 2013;120:1719.

    Google Scholar 

  92. Byar DP, Schoenfeld DA, Green SB, et al. Design considerations for AIDS trials. N Engl J Med 1990;323:1343–1348.

    Article  Google Scholar 

  93. Levine C, Dubler NN, Levine RJ. Building a new consensus: ethical principles and policies for clinical research on HIV/AIDS. IRB 1991;13:1–17.

    Article  Google Scholar 

  94. Spiers HR. Community consultation and AIDS clinical trials, part I. IRB 1991;13:7–10.

    Article  Google Scholar 

  95. Emanuel EJ, Grady C. Four paradigms of clinical research and research oversight. In: The Oxford Textbook of Clinical Research Ethics. EJ Emamuel, C Grady, RA Crouch, RK Lie, FG Miller, D Wendler (Eds.). Oxford: Oxford University Press, 2008, pages 222–230.

    Chapter  Google Scholar 

  96. Abigail Alliance For Better Access to Developmental Drugs. http://abigail-alliance.org/.

  97. Diacon AH, Pym A, Grobusch MP, et al. Multidrug-resistant tuberculosis and culture conversion with bedaquiline. N Engl J Med 2014;371:723–732.

    Article  Google Scholar 

  98. Cox E, Laessig K. FDA approval of bedaquiline—the benefit-risk balance for drug-resistant tuberculosis. N Engl J Med 2014;371:689–691.

    Article  Google Scholar 

  99. Furberg CD. The impact of clinical trials on clinical practice. Arzneim-Forsch./Drug Res 1989;39:986–988.

    Google Scholar 

  100. Lamas GA, Pfeffer MA, Hamm P, et al. Do the results of randomized clinical trials of cardiovascular drugs influence medical practice? N Engl J Med 1992;327:241–247.

    Article  Google Scholar 

  101. Friedman L, Wenger NK, Knatterud GL. Impact of the Coronary Drug Project findings on clinical practice. Control Clin Trials 1983;4:513–522.

    Article  Google Scholar 

  102. Boissel JP. Impact of randomized clinical trials on medical practices. Control Clin Trials 1989;10:120S–134S.

    Article  Google Scholar 

  103. Schron E, Rosenberg Y, Parker A, Stylianou M. Awareness of clinical trials results and influence on prescription behavior: A survey of US Physicians. Control Clin Trials 1994;15:108S.

    Article  Google Scholar 

  104. Ayanian JZ, Haustman PJ, Guadagnoli E, et al. Knowledge and practices of generalist and specialist physicians regarding drug therapy for acute myocardial infarction. N Engl J Med 1994;331:1136–1142.

    Article  Google Scholar 

  105. Ford ES, Ajani UA, Croft JB, et al. Explaining the decrease in U.S. deaths from coronary disease, 1980-2000. N Engl J Med 2007;356:2388–2398.

    Article  Google Scholar 

  106. Jernberg T, Hohanson P, Held C, et al. Association between adoption of evidence-based treatment and survival for patients with ST-elevation myocardial infarction. JAMA 2011;305:1677–1684.

    Article  Google Scholar 

  107. Peterson ED, Roe MT, Mulgund J, et al. Association between hospital process performance and outcomes among patients with acute coronary syndromes. JAMA 2006;295:1912–1920.

    Article  Google Scholar 

  108. Benson K, Hartz AJ. A comparison of observational studies and randomized, controlled trials. N Engl J Med 2000;342:1878–1886.

    Article  Google Scholar 

  109. Concato J, Shah N, Horwitz RI. Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med 2000;342:1887–1892.

    Article  Google Scholar 

  110. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA 2007;297:842–857.

    Article  Google Scholar 

  111. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605–613.

    Article  Google Scholar 

  112. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002;288:321–333.

    Article  Google Scholar 

  113. 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 

  114. Granger CB, McMurray JJV. Using measures of disease progression to determine therapeutic effect: a sirens’ song. J Am Coll Cardiol 2006;48:434–437.

    Article  Google Scholar 

  115. Furberg BD, Furberg CD. Evaluating Clinical Research: All that Glitters is not Gold. (Second ed.) New York: Springer, 2007.

    Google Scholar 

  116. Chalmers TC. Randomization of the first patient. Med Clin North Am 1975;59:1035–1038.

    Article  Google Scholar 

  117. Spodick DH. Randomize the first patient: scientific, ethical, and behavioral bases. Am J Cardiol 1983;51:916–917.

    Article  Google Scholar 

  118. Bonchek LI. Sounding Board: Are randomized trials appropriate for evaluating new operations? N Engl J Med 1979;301:44–45.

    Article  Google Scholar 

  119. Van der Linden W. Pitfalls in randomized surgical trials. Surgery 1980;87:258–262.

    Google Scholar 

  120. Rudicel S, Esdail J. The randomized clinical trial in orthopaedics: obligation or option? J Bone Joint Surg 1985;67:1284–1293.

    Article  Google Scholar 

  121. Murphy ML, Hultgren HN, Detre K, et al. Treatment of chronic stable angina - a preliminary report of survival data of the randomized Veterans Administration cooperative study. N Engl J Med 1977;297:621–627.

    Article  Google Scholar 

  122. Takaro T, Hultgren HN, Lipton MJ, Detre KM. The VA cooperative randomized study of surgery for coronary arterial occlusive disease. 11. Subgroup with significant left main lesions. Circulation 1976;54:111–107.

    Google Scholar 

  123. Detre K, Peduzzi P, Murphy M, et al. Effect of bypass surgery on survival in patients in low- and high-risk subgroups delineated by the use of simple clinical variables. Circulation 1981;63:1329–1338.

    Article  Google Scholar 

  124. Proudfit WL. Criticisms of the VA randomized study of coronary bypass surgery. Clin Res 1978;26:236–240.

    Google Scholar 

  125. Chalmers TC, Smith H Jr, Ambroz A, et al. In defense of the VA randomized control trial of coronary artery surgery. Clin Res 1978;26:230–235.

    Google Scholar 

  126. CASS Principal Investigators and their Associates. Myocardial infarction and mortality in the Coronary Artery Surgery Study (CASS) randomized trial. N Engl J Med 1984;310:750–758.

    Article  Google Scholar 

  127. Cutlip DE, Balm DS, Kalon KL, et al. Stent thrombosis in the modern era: a pooled analysis of multicenter coronary stent clinical trials. Circulation 2001;103:1967–1971.

    Article  Google Scholar 

  128. Babapulle MN, Joseph L, Bélisle P, Brophy JM, Eisenberg MJ. A hierarchical Bayesian meta-analysis of randomised clinical trials of drug-eluting stents. Lancet 2004;364:14–20.

    Article  Google Scholar 

  129. Strachan CJL,Oates GD. Surgical trials. F.N. Johnson and S. Johnson (Eds). In: Clinical Trials. Oxford: Blackwell Scientific: 1977.

    Google Scholar 

  130. Bunker JP, Hinkley D, McDermott WV. Surgical innovation and its evaluation. Science 1978;200:937–941.

    Article  Google Scholar 

  131. Weil RJ. The future of surgical research. PLoS Med 2004;1:e13. doi:10.1371/journal.pmed.0010013.

    Article  Google Scholar 

  132. Cook JA. The challenges faced in the design, conduct and analysis of surgical randomised controlled trials. Trials 2009. 10:9doi:10.1186/1745-6215-10-9.

  133. Chalmers TC, Sacks H. Letter to the editor: Randomized clinical trials in surgery. N Engl J Med 1979;301:1182.

    Google Scholar 

  134. Greene HL, Roden DM, Katz RJ, et al. The Cardiac Arrhythmia Suppression Trial: first CAST…then CAST-II. J Am Coll Cardiol 1992;19:894–898.

    Article  Google Scholar 

  135. World Health Organization International Clinical Trials Registry Platform Search Portal. http://apps.who.int/trialsearch/

  136. ClinicalTrials.gov. http://clinicaltrials.gov/

  137. Clinical Trials Registration in ClinicalTrials.gov (Public Law 110-85): Competing Applications and Non-Competing Progress Reports. http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-023.html.

  138. Federal Register: May 21, 2008 (Volume 73, Number 99). http://edocket.access.gpo.gov/2008/E8-11042.htm

  139. Califf RM, Zarin DA, Kramer JM, et al. Characteristics of clinical trials registered in ClinicalTrials.gov, 2007-2010. JAMA. 2012;307:1838–1847. doi: 10.1001/jama.2012.3424.

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

Appendices

Appendices

Definitions of eligibility criteria

Definitions of response variables

Informed Consent Form

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). Introduction to Clinical Trials. In: Fundamentals of Clinical Trials. Springer, Cham. https://doi.org/10.1007/978-3-319-18539-2_1

Download citation

Publish with us

Policies and ethics

Search

Navigation