A Focus on Clinical Trials

  • Stephen P. GlasserEmail author


The spectrum of evidence imparted by the different clinical research designs ranges from ecological studies through observational epidemiological studies to randomized control trials (RCTs). This chapter addresses the definition of clinical research, the major aspects of clinical trials e.g. ethics, randomization, masking, recruitment and retention of subjects enrolled in a clinical trial, patients/subjects lost to follow-up during the trial etc. Although this chapter focuses on the weaknesses of clinical trials, it is emphasized that the randomized, placebo-controlled, double blind clinical trial is the design that yields the greatest level of scientific evidence.


Generalizability/external validity. Internal validity Superiority testing Equivalence/noninferiority testing Randomization Intention to treat Missing data Eligibility Efficacy/effectiveness Blinding/masking Subgroup analysis Surrogate endpoints Composite endpoints Primary and secondary endpoints 


  1. 1.
    Glasser SP, Howard G. Clinical trial design issues: at least 10 things you should look for in clinical trials. J Clin Pharmacol. 2006;46:1106–15.PubMedCrossRefGoogle Scholar
  2. 2.
    Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA. 2002;288:49–57.PubMedCrossRefGoogle Scholar
  3. 3.
    Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998;280:605–13.PubMedCrossRefGoogle Scholar
  4. 4.
    Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288:321–33.PubMedCrossRefGoogle Scholar
  5. 5.
    Grady D, Rubin SM, Petitti DB, Fox CS, Black D, Ettinger B, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med. 1992;117:1016–37.PubMedCrossRefGoogle Scholar
  6. 6.
    Stampfer MJ, Colditz GA. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med. 1991;20:47–63.PubMedCrossRefGoogle Scholar
  7. 7.
    Sullivan JM, Vander Zwaag R, Hughes JP, Maddock V, Kroetz FW, Ramanathan KB, et al. Estrogen replacement and coronary artery disease. Effect on survival in postmenopausal women. Arch Intern Med. 1990;150:2557–62.PubMedCrossRefGoogle Scholar
  8. 8.
    Bhatt DL, Cavender MA. Are all clinical trial sites created equal? J Am Coll Cardiol. 2013;61:580–1. doi: 10.1016/j.jacc.2012.10.024.PubMedCrossRefGoogle Scholar
  9. 9.
    Little RJ, D’Agostino R, Cohen ML, Dickersin K, Emerson SS, Farrar JT, et al. The prevention and treatment of missing data in clinical trials. N Engl J Med. 2012;367:1355–60. PMC3771340.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Butler J, Subacius H, Vaduganathan M, Fonarow GC, Ambrosy AP, Konstam MA, et al. Relationship between clinical trial site enrollment with participant characteristics, protocol completion, and outcomes: insights from the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) trial. J Am Coll Cardiol. 2013;61:571–9. doi: 10.1016/j.jacc.2012.10.025.PubMedCrossRefGoogle Scholar
  11. 11.
    Grimes DA, Schulz KF. An overview of clinical research: the lay of the land. Lancet. 2002;359:57–61.PubMedCrossRefGoogle Scholar
  12. 12.
    Loscalzo J. Clinical trials in cardiovascular medicine in an era of marginal benefit, bias, and hyperbole. Circulation. 2005;112:3026–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Bienenfeld L, Frishman W, Glasser SP. The placebo effect in cardiovascular disease. Am Heart J. 1996;132:1207–21.PubMedCrossRefGoogle Scholar
  14. 14.
    Clark PI, Leaverton PE. Scientific and ethical issues in the use of placebo controls in clinical trials. Annu Rev Public Health. 1994;15:19–38.PubMedCrossRefGoogle Scholar
  15. 15.
    Rothman KJ, Michels KB. The continuing unethical use of placebo controls. N Engl J Med. 1994;331:394–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Montori VM, Devereaux PJ, Adhikari NK, Burns KE, Eggert CH, Briel M, et al. Randomized trials stopped early for benefit: a systematic review. JAMA. 2005;294:2203–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Medical Research Council. Streptomycin treatment of pulmonary tuberculosis. BMJ. 1948;ii:769–82.Google Scholar
  18. 18.
    Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika. 1983;70:41–55.CrossRefGoogle Scholar
  19. 19.
    Gum PA, Thamilarasan M, Watanabe J, Blackstone EH, Lauer MS. Aspirin use and all-cause mortality among patients being evaluated for known or suspected coronary artery disease: a propensity analysis. JAMA. 2001;286:1187–94.PubMedCrossRefGoogle Scholar
  20. 20.
    Reviews of statistical and economic books, Student’s Collected Papers. J R Stat Soc. 1943;106:278–9.Google Scholar
  21. 21.
    Fleming TR. Addressing missing data in clinical trials. Ann Intern Med. 2010;154:113–7. PMC3319761.CrossRefGoogle Scholar
  22. 22.
    A Village of 100 In. 2nd ATS Media ed: A Step Ahead.Google Scholar
  23. 23.
    North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med. 1991;325:445–53.CrossRefGoogle Scholar
  24. 24.
    Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid artery stenosis. JAMA. 1995;273:1421–8.CrossRefGoogle Scholar
  25. 25.
    Lang JM. The use of a run-in to enhance compliance. Stat Med. 1990;9:87–93; discussion −5.PubMedCrossRefGoogle Scholar
  26. 26.
    Franciosa JA. Commentary on the use of run-in periods in clinical trials. Am J Cardiol. 1999;83:942–4. A9.PubMedCrossRefGoogle Scholar
  27. 27.
    Pablos-Mendez A, Barr RG, Shea S. Run-in periods in randomized trials: implications for the application of results in clinical practice. JAMA. 1998;279:222–5.PubMedCrossRefGoogle Scholar
  28. 28.
    Schulz KF, Grimes DA. Blinding in randomised trials: hiding who got what. Lancet. 2002;359:696–700.PubMedCrossRefGoogle Scholar
  29. 29.
    Shem S. The house of god. In: Palgrave Macmillan; 1978:280.Google Scholar
  30. 30.
    Smith DH, Neutel JM, Lacourciere Y, Kempthorne-Rawson J. Prospective, randomized, open-label, blinded-endpoint (PROBE) designed trials yield the same results as double-blind, placebo-controlled trials with respect to ABPM measurements. J Hypertens. 2003;21:1291–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Multiple Risk Factor Intervention Trial Research Group. Multiple risk factor intervention trial. Risk factor changes and mortality results. JAMA. 1982;248:1465–77.CrossRefGoogle Scholar
  32. 32.
    Mayo E. The human problems of an industrial civilization. New York: Macmillan; 1993.Google Scholar
  33. 33.
    Alpha-Tocopherol T, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med. 1994;330:1029–35.CrossRefGoogle Scholar
  34. 34.
    Hollis S, Campbell F. What is meant by intention to treat analysis? Survey of published randomised controlled trials. BMJ. 1999;319:670–4.PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    The Coronary Drug Project Research Group. Influence of adherence to treatment and response of cholesterol on mortality in the coronary drug project. N Engl J Med. 1980;303:1038–41.CrossRefGoogle Scholar
  36. 36.
    The Anturane Reinfarction Trial Research Group. Sulfinpyrazone in the prevention of sudden death after myocardial infarction. N Engl J Med. 1980;302:250–6.CrossRefGoogle Scholar
  37. 37.
    Sackett DL, Gent M. Controversy in counting and attributing events in clinical trials. N Engl J Med. 1979;301:1410–2.PubMedCrossRefGoogle Scholar
  38. 38.
    Howard G, Chambless LE, Kronmal RA. Assessing differences in clinical trials comparing surgical vs nonsurgical therapy: using common (statistical) sense. JAMA. 1997;278:1432–6.PubMedCrossRefGoogle Scholar
  39. 39.
    Assmann SF, Pocock SJ, Enos LE, Kasten LE. Subgroup analysis and other (mis)uses of baseline data in clinical trials. Lancet. 2000;355:1064–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Sleight P. Debate: subgroup analyses in clinical trials: fun to look at – but don’t believe them! Curr Control Trials Cardiovasc Med. 2000;1:25–7.PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Amarenco P, Goldstein LB, Szarek M, Sillesen H, Rudolph AE, Callahan 3rd A, et al. Effects of intense low-density lipoprotein cholesterol reduction in patients with stroke or transient ischemic attack: the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Stroke. 2007;38:3198–204.PubMedCrossRefGoogle Scholar
  42. 42.
    Black HR, Elliott WJ, Grandits G, Grambsch P, Lucente T, White WB, et al. Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial. JAMA. 2003;289:2073–82.PubMedCrossRefGoogle Scholar
  43. 43.
    Weir MR, Ferdinand KC, Flack JM, Jamerson KA, Daley W, Zelenkofske S. A noninferiority comparison of valsartan/hydrochlorothiazide combination versus amlodipine in black hypertensives. Hypertension. 2005;46:508–13.PubMedCrossRefGoogle Scholar
  44. 44.
    Kaul S, Diamond GA, Weintraub WS. Trials and tribulations of non-inferiority: the ximelagatran experience. J Am Coll Cardiol. 2005;46:1986–95.PubMedCrossRefGoogle Scholar
  45. 45.
    Le Henanff A, Giraudeau B, Baron G, Ravaud P. Quality of reporting of noninferiority and equivalence randomized trials. JAMA. 2006;295:1147–51.PubMedCrossRefGoogle Scholar
  46. 46.
    Halanych JH, Shuaib F, Parmar G, Tanikella R, Howard VJ, Roth DL, et al. Agreement on cause of death between proxies, death certificates, and clinician adjudicators in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. Am J Epidemiol. 2011;173:1319–26. PMC3101067.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med. 1996;125:605–13.PubMedCrossRefGoogle Scholar
  48. 48.
    Prentice RL. Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med. 1989;8:431–40.PubMedCrossRefGoogle Scholar
  49. 49.
    Anand IS, Florea VG, Fisher L. Surrogate end points in heart failure. J Am Coll Cardiol. 2002;39:1414–21.PubMedCrossRefGoogle Scholar
  50. 50.
    Kelsen DP. Surrogate endpoints in assessment of new drugs in colorectal cancer. Lancet. 2000;356:353–4.PubMedCrossRefGoogle Scholar
  51. 51.
    Buyse M, Thirion P, Carlson RW, Burzykowski T, Molenberghs G, Piedbois P. Relation between tumour response to first-line chemotherapy and survival in advanced colorectal cancer: a meta-analysis. Meta-Analysis Group in Cancer. Lancet. 2000;356:373–8.PubMedCrossRefGoogle Scholar
  52. 52.
    Greene HL, Roden DM, Katz RJ, Woosley RL, Salerno DM, Henthorn RW. The Cardiac Arrhythmia Suppression Trial: first CAST… then CAST-II. J Am Coll Cardiol. 1992;19:894–8.PubMedCrossRefGoogle Scholar
  53. 53.
    FDA Adviser Questions Surrogate Endpoints for Diabetes Drug Approvals. In: Medpage Today; 2007.Google Scholar
  54. 54.
    Boissel JP, Collet JP, Moleur P, Haugh M. Surrogate endpoints: a basis for a rational approach. Eur J Clin Pharmacol. 1992;43:235–44.PubMedCrossRefGoogle Scholar
  55. 55.
    O'Neill RT. Secondary endpoints cannot be validly analyzed if the primary endpoint does not demonstrate clear statistical significance. Control Clin Trials. 1997;18:550–6. discussion 61–7.PubMedCrossRefGoogle Scholar
  56. 56.
    Armstrong PW, Westerhout CM. The power of more than one. Circulation. 2013;127:665–7. doi: 10.1161/CIRCULATIONAHA.112.000627.PubMedCrossRefGoogle Scholar
  57. 57.
    Montori VM, Busse JW, Permanyer-Miralda G, Ferreira I, Guyatt GH. How should clinicians interpret results reflecting the effect of an intervention on composite endpoints: should I dump this lump? ACP J Club. 2005;143:A8.PubMedGoogle Scholar
  58. 58.
    Freemantle N, Calvert M, Wood J, Eastaugh J, Griffin C. Composite outcomes in randomized trials: greater precision but with greater uncertainty? JAMA. 2003;289:2554–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Lauer MS, Topol EJ. Clinical trials – multiple treatments, multiple end points, and multiple lessons. JAMA. 2003;289:2575–7.PubMedCrossRefGoogle Scholar
  60. 60.
    Kip KE, Hollabaugh K, Marroquin OC, Williams DO. The problem with composite end points in cardiovascular studies. J Am Coll Cardiol. 2008;51:701–7. doi: 10.1016/j.jacc.2007.10.034.PubMedCrossRefGoogle Scholar
  61. 61.
    Bethel MA, Holman R, Haffner SM, Califf RM, Huntsman-Labed A, Hua TA, et al. Determining the most appropriate components for a composite clinical trial outcome. Am Heart J. 2008;156:633–40. doi: 10.1016/j.ahj.2008.05.018.PubMedCrossRefGoogle Scholar
  62. 62.
    Granger CB, Vogel V, Cummings SR, Held P, Fiedorek F, Lawrence M, et al. Do we need to adjudicate major clinical events? Clin Trials. 2008;5:56–60. doi: 10.1177/1740774507087972.PubMedCrossRefGoogle Scholar
  63. 63.
    Connolly SJ, Gent M, Roberts RS, Dorian P, Roy D, Sheldon RS, et al. Canadian implantable defibrillator study (CIDS): a randomized trial of the implantable cardioverter defibrillator against amiodarone. Circulation. 2000;101:1297–302.PubMedCrossRefGoogle Scholar
  64. 64.
    Bokhari F, Newman D, Greene M, Korley V, Mangat I, Dorian P. Long-term comparison of the implantable cardioverter defibrillator versus amiodarone: eleven-year follow-up of a subset of patients in the Canadian Implantable Defibrillator Study (CIDS). Circulation. 2004;110:112–6.PubMedCrossRefGoogle Scholar
  65. 65.
    Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001;285:1711–8.PubMedCrossRefGoogle Scholar
  66. 66.
    The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the antihypertensive and lipid lowering treatment to prevent heart attack trial (ALLHAT). JAMA 2002;288:2981–97.Google Scholar
  67. 67.
    Starzl TE, Donner A, Eliasziw M, Stitt L, Meier P, Fung JJ, et al. Randomised trialomania? The multicentre liver transplant trials of tacrolimus. Lancet. 1995;346:1346–50.PubMedCentralPubMedCrossRefGoogle Scholar
  68. 68.
    Ioannidis JPA. Why most published research findings are false. PLoS. 2005;2:696–701.Google Scholar
  69. 69.
    Kaul S, Diamond GA. Trial and error. How to avoid commonly encountered limitations of published clinical trials. J Am Coll Cardiol. 2010;55:415–27. doi: 10.1016/j.jacc.2009.06.065.PubMedCrossRefGoogle Scholar
  70. 70.
    Goodman SA. A dirty dozen: Twelve P-value misconceptions. Semin Hematol. 2008;45:135–40. doi: 10.1053/j.seminhematol.2008.04.003.PubMedCrossRefGoogle Scholar
  71. 71.
    Toma M, McAlister FA, Bialy L, Adams D, Vandermeer B, Armstrong PW. Transition from meeting abstract to full-length journal article for randomized controlled trials. JAMA. 2006;295:1281–7.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  1. 1.Division of Preventive MedicineUniversity of Alabama at BirminghamBirminghamUSA

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