Skip to main content
SpringerLink
Log in

A Focus on Clinical Trials

  • Chapter
  • First Online:
Essentials of Clinical Research

  • 5886 Accesses

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 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.

A researcher is in a gondola of a balloon that loses lift and lands in the middle of a field 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’s amazing, how did you know?’ ‘Your answer was correct and precise and totally useless.’ (ANON)

Less than 50 % of this chapter is taken from “Clinical trial design issues: at least 10 things you should look for in clinical trials” [1] with permission of the publisher.

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

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 129.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 129.99
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. 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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  11. Grimes DA, Schulz KF. An overview of clinical research: the lay of the land. Lancet. 2002;359:57–61.

    Article  PubMed  Google Scholar 

  12. Loscalzo J. Clinical trials in cardiovascular medicine in an era of marginal benefit, bias, and hyperbole. Circulation. 2005;112:3026–9.

    Article  PubMed  Google Scholar 

  13. Bienenfeld L, Frishman W, Glasser SP. The placebo effect in cardiovascular disease. Am Heart J. 1996;132:1207–21.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  15. Rothman KJ, Michels KB. The continuing unethical use of placebo controls. N Engl J Med. 1994;331:394–8.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  17. Medical Research Council. Streptomycin treatment of pulmonary tuberculosis. BMJ. 1948;ii:769–82.

    Google Scholar 

  18. Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika. 1983;70:41–55.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  20. Reviews of statistical and economic books, Student’s Collected Papers. J R Stat Soc. 1943;106:278–9.

    Google Scholar 

  21. Fleming TR. Addressing missing data in clinical trials. Ann Intern Med. 2010;154:113–7. PMC3319761.

    Article  Google Scholar 

  22. A Village of 100 In. 2nd ATS Media ed: A Step Ahead.

    Google Scholar 

  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.

    Article  Google Scholar 

  24. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid artery stenosis. JAMA. 1995;273:1421–8.

    Article  Google Scholar 

  25. Lang JM. The use of a run-in to enhance compliance. Stat Med. 1990;9:87–93; discussion −5.

    Article  CAS  PubMed  Google Scholar 

  26. Franciosa JA. Commentary on the use of run-in periods in clinical trials. Am J Cardiol. 1999;83:942–4. A9.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  28. Schulz KF, Grimes DA. Blinding in randomised trials: hiding who got what. Lancet. 2002;359:696–700.

    Article  PubMed  Google Scholar 

  29. Shem S. The house of god. In: Palgrave Macmillan; 1978:280.

    Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  31. Multiple Risk Factor Intervention Trial Research Group. Multiple risk factor intervention trial. Risk factor changes and mortality results. JAMA. 1982;248:1465–77.

    Article  Google Scholar 

  32. Mayo E. The human problems of an industrial civilization. New York: Macmillan; 1993.

    Google Scholar 

  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.

    Article  Google Scholar 

  34. Hollis S, Campbell F. What is meant by intention to treat analysis? Survey of published randomised controlled trials. BMJ. 1999;319:670–4.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  Google Scholar 

  37. Sackett DL, Gent M. Controversy in counting and attributing events in clinical trials. N Engl J Med. 1979;301:1410–2.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed Central  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  44. Kaul S, Diamond GA, Weintraub WS. Trials and tribulations of non-inferiority: the ximelagatran experience. J Am Coll Cardiol. 2005;46:1986–95.

    Article  PubMed  Google Scholar 

  45. Le Henanff A, Giraudeau B, Baron G, Ravaud P. Quality of reporting of noninferiority and equivalence randomized trials. JAMA. 2006;295:1147–51.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed Central  PubMed  Google Scholar 

  47. Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med. 1996;125:605–13.

    Article  CAS  PubMed  Google Scholar 

  48. Prentice RL. Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med. 1989;8:431–40.

    Article  CAS  PubMed  Google Scholar 

  49. Anand IS, Florea VG, Fisher L. Surrogate end points in heart failure. J Am Coll Cardiol. 2002;39:1414–21.

    Article  PubMed  Google Scholar 

  50. Kelsen DP. Surrogate endpoints in assessment of new drugs in colorectal cancer. Lancet. 2000;356:353–4.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  53. FDA Adviser Questions Surrogate Endpoints for Diabetes Drug Approvals. In: Medpage Today; 2007.

    Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  56. Armstrong PW, Westerhout CM. The power of more than one. Circulation. 2013;127:665–7. doi:10.1161/CIRCULATIONAHA.112.000627.

    Article  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  59. Lauer MS, Topol EJ. Clinical trials – multiple treatments, multiple end points, and multiple lessons. JAMA. 2003;289:2575–7.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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. 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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  68. Ioannidis JPA. Why most published research findings are false. PLoS. 2005;2:696–701.

    Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  70. Goodman SA. A dirty dozen: Twelve P-value misconceptions. Semin Hematol. 2008;45:135–40. doi:10.1053/j.seminhematol.2008.04.003.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Preventive Medicine, University of Alabama at Birmingham, 1717 11th Ave S MT638, Birmingham, AL, 35205, USA

    Stephen P. Glasser M.D.

Authors
  1. Stephen P. Glasser M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stephen P. Glasser M.D. .

Editor information

Editors and Affiliations

  1. Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Stephen P. Glasser

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Glasser, S.P. (2014). A Focus on Clinical Trials. In: Glasser, S. (eds) Essentials of Clinical Research. Springer, Cham. https://doi.org/10.1007/978-3-319-05470-4_3

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-05470-4_3

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-05469-8

  • Online ISBN: 978-3-319-05470-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation