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Abstract

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 eg 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, placebocontrolled, double blind clinical trial is the design that yields the greatest level of scientific evidence.

A researcher is in a gondola of a balloon that loses lift and lands in the middle of afield near a road. Of course, it looks like the balloon landed in the middle of nowhere. As the researcher ponders appropriate courses of action, another person wanders by. The researcher asks, ‘Where am I?’ The other person responds, ‘You are in the gondola of a balloon in the middle of a field.’ The researcher comments, ‘You must design clinical trials.’ ‘Well, that’ amazing, how did you know?’ ‘Your answer was correct and precise and totally useless.’

Keywords

Major Adverse Cardiac Event Composite Endpoint Surrogate Endpoint Beta Carotene Multiple Risk Factor Intervention Trial 
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.
    Grady D, Herrington D, Bittner V, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). Jama. Jul 3 2002;288(1):49-57.PubMedCrossRefGoogle Scholar
  2. 2.
    Hulley S, Grady D, Bush T, 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. Aug 19 1998;280(7):605–613.PubMedCrossRefGoogle Scholar
  3. 3.
    Rossouw JE, Anderson GL, Prentice RL, 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. Jul 17 2002;288(3):321–333.PubMedCrossRefGoogle Scholar
  4. 4.
    Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med. Dec 15 1992;117(12):1016–1037.PubMedGoogle Scholar
  5. 5.
    Stampfer MJ, Colditz GA. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med. Jan 1991;20(1):47–63.PubMedCrossRefGoogle Scholar
  6. 6.
    Sullivan JM, Vander Zwaag R, Hughes JP, et al. Estrogen replacement and coronary artery disease. Effect on survival in postmenopausal women. Arch Intern Med. Dec 1990;150(12):2557–2562.PubMedCrossRefGoogle Scholar
  7. 7.
    Glasser SP, Howard G. Clinical trial design issues: at least 10 things you should look for in clinical trials. J Clin Pharmacol. Oct 2006;46(10):1106–1115.PubMedCrossRefGoogle Scholar
  8. 8.
    Grimes DA, Schulz KF. An overview of clinical research: the lay of the land. Lancet. Jan 5 2002;359(9300):57–61.PubMedCrossRefGoogle Scholar
  9. 9.
    Loscalzo J. Clinical trials in cardiovascular medicine in an era of marginal benefit, bias, and hyperbole. Circulation. Nov 15 2005;112(20):3026–3029.PubMedCrossRefGoogle Scholar
  10. 10.
    Bienenfeld L, Frishman W, Glasser SP. The placebo effect in cardiovascular disease. Am Heart J. Dec 1996;132(6):1207–1221.PubMedCrossRefGoogle Scholar
  11. 11.
    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
  12. 12.
    Rothman KJ, Michels KB. The continuing unethical use of placebo controls. N Engl J Med. Aug 11 1994;331(6):394–398.PubMedCrossRefGoogle Scholar
  13. 13.
    Montori VM, Devereaux PJ, Adhikari NK, et al. Randomized trials stopped early for benefit: a systematic review. Jama. Nov 2 2005;294(17):2203–2209.PubMedCrossRefGoogle Scholar
  14. 14.
    Medical Research Council. Streptomycin treatment of pulmonary tuberculosis. BMJ. 1948;ii:769–782.Google Scholar
  15. 15.
    Reviews of statistical and economic books, Student’s Collected Papers. J Royal Staitistical Society. 1943;106:278–279.CrossRefGoogle Scholar
  16. 16.
    A Village of 100 A Step Ahead.Google Scholar
  17. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med. Aug 15 1991;325(7):445–453.Google Scholar
  18. 18.
    Endarterectomy for asymptomatic carotid artery stenosis. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Jama. May 10 1995;273(18):1421–1428.CrossRefGoogle Scholar
  19. 19.
    Lang JM. The use of a run-in to enhance compliance. Stat Med. Jan-Feb 1990;9(1–2):87–93; discussion 93–85.PubMedCrossRefGoogle Scholar
  20. 20.
    Shem S. The House of God: Palgrace Macmillan; 1978:280.Google Scholar
  21. 21.
    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. Jul 2003;21(7):1291–1298.PubMedCrossRefGoogle Scholar
  22. Multiple risk factor intervention trial. Risk factor changes and mortality results. Multiple Risk Factor Intervention Trial Research Group. Jama. Sep 24 1982;248(12):1465–1477.Google Scholar
  23. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med. Apr 14 1994;330(15):1029–1035.Google Scholar
  24. 24.
    Hollis S, Campbell F. What is meant by intention to treat analysis? Survey of published randomised controlled trials. Bmj. Sep 11 1999;319(7211):670–674.PubMedGoogle Scholar
  25. 25.
    Influence of adherence to treatment and response of cholesterol on mortality in the coronary drug project. N Engl J Med. Oct 30 1980;303(18):1038–1041.Google Scholar
  26. Sulfinpyrazone in the prevention of sudden death after myocardial infarction. The Anturane Reinfarction Trial Research Group. N Engl J Med. Jan 31 1980;302(5):250–256.Google Scholar
  27. 27.
    Sackett DL, Gent M. Controversy in counting and attributing events in clinical trials. N Engl J Med. Dec 27 1979;301(26):1410–1412.PubMedCrossRefGoogle Scholar
  28. 28.
    Howard G, Chambless LE, Kronmal RA. Assessing differences in clinical trials comparing surgical vs nonsurgical therapy: using common (statistical) sense. Jama. Nov 5 1997;278(17):1432–1436.PubMedCrossRefGoogle Scholar
  29. 29.
    Assmann SF, Pocock SJ, Enos LE, Kasten LE. Subgroup analysis and other (mis) uses of baseline data in clinical trials. Lancet. Mar 25 2000;355(9209):1064–1069.PubMedCrossRefGoogle Scholar
  30. 30.
    Sleight P. Debate: Subgroup analyses in clinical trials: fun to look at - but don’t believe them! Curr Control Trials Cardiovasc med. 2000;1(1):25–27.PubMedCrossRefGoogle Scholar
  31. 31.
    Amarenco P, Goldstein LB, Szarek M, 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. Dec 2007;38(12): 3198–3204.PubMedCrossRefGoogle Scholar
  32. 32.
    Black HR, Elliott WJ, Grandits G, et al. Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial. Jama. Apr 23–30 2003;289(16):2073–2082.PubMedCrossRefGoogle Scholar
  33. 33.
    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. Sep 2005;46(3):508–513.PubMedCrossRefGoogle Scholar
  34. 34.
    Kaul S, Diamond GA, Weintraub WS. Trials and tribulations of non-inferiority: the ximelagatran experience. J Am Coll Cardiol. Dec 6 2005;46(11):1986–1995.PubMedCrossRefGoogle Scholar
  35. 35.
    Le Henanff A, Giraudeau B, Baron G, Ravaud P. Quality of reporting of noninferiority and equivalence randomized trials. Jama. Mar 8 2006;295(10):1147–1151.PubMedCrossRefGoogle Scholar
  36. 36.
    Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med. Oct 1 1996;125(7):605–613.PubMedGoogle Scholar
  37. 37.
    Prentice RL. Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med. Apr 1989;8(4):431–440.PubMedCrossRefGoogle Scholar
  38. 38.
    Anand IS, Florea VG, Fisher L. Surrogate end points in heart failure. J Am Coll Cardiol. May 1 2002;39(9):1414–1421.PubMedCrossRefGoogle Scholar
  39. 39.
    Kelsen DP. Surrogate endpoints in assessment of new drugs in colorectal cancer. Lancet. Jul 29 2000;356(9227):353–354.PubMedCrossRefGoogle Scholar
  40. 40.
    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. Jul 29 2000;356(9227):373–378.PubMedCrossRefGoogle Scholar
  41. 41.
    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. Apr 1992;19(5):894–898.PubMedGoogle Scholar
  42. 42.
    FDA Adviser Questions Surrogate Endpoints for Diabetes Drug Approvals. Medpage Today; 2007.Google Scholar
  43. 43.
    Boissel JP, Collet JP, Moleur P, Haugh M. Surrogate endpoints: a basis for a rational approach. Eur J Clin Pharmacol. 1992;43(3):235–244.PubMedCrossRefGoogle Scholar
  44. 44.
    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. Nov-Dec 2005;143(3):A8.PubMedGoogle Scholar
  45. 45.
    Freemantle N, Calvert M, Wood J, Eastaugh J, Griffin C. Composite outcomes in randomized trials: greater precision but with greater uncertainty? Jama. May 21 2003;289(19):2554–2559.CrossRefGoogle Scholar
  46. 46.
    Lauer MS, Topol EJ. Clinical trials–multiple treatments, multiple end points, and multiple lessons. Jama. May 21 2003;289(19):2575–2577.PubMedCrossRefGoogle Scholar
  47. 47.
    Kip K, Hollabaugh K, Marroquin O, Williams D. The problem with composite endpoinmts in cardiovascular studies. J Am Coll Cardiol. 2008;51:701–707.PubMedCrossRefGoogle Scholar
  48. 48.
    Connolly SJ, Gent M, Roberts RS, et al. Canadian implantable defibrillator study (CIDS) : a randomized trial of the implantable cardioverter defibrillator against amiodarone. Circulation. Mar 21 2000;101(11):1297–1302.PubMedGoogle Scholar
  49. 49.
    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. Jul 13 2004;110(2):112–116.PubMedCrossRefGoogle Scholar
  50. 50.
    Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. Jama. Apr 4 2001;285(13):1711–1718.PubMedCrossRefGoogle Scholar
  51. 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. Dec 18 2002;288(23):2981–2997.Google Scholar
  52. 52.
    Starzl TE, Donner A, Eliasziw M, et al. Randomised trialomania? The multicentre liver transplant trials of tacrolimus. Lancet. Nov 18 1995;346(8986):1346–1350.PubMedCrossRefGoogle Scholar
  53. 53.
    Ioannidis JPA. Why most published research findings are false. PLoS. 2005;2:0696–0701.Google Scholar
  54. 54.
    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. Mar 15 2006;295(11):1281–1287.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media B.V 2008

Authors and Affiliations

  • Stephen P. Glasser
    • 1
  1. 1.Univesity of Alabama at Birmingham, Birmingham, AlabamaBirmingham

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