Randomized controlled trials stand among the most significant advances in medical research in recent times, and in a span of less than 60 years have revolutionized care for a large number of disease. As biomedical technology and knowledge continues to advance at a record pace, this effort must grow and diversity to meet the need for objective, high quality evidence regarding the merits of new interventions.
References
1. Allison JJ, Kiefe CI, Weissman NW, et al. Relationship of hospital teaching status with quality of care and mortality for Medicare patients with acute MI. JAMA.
2000;284:1256-1262.
2. Bernard CL. Introduction á l’Edude de la Médecine Expérimentale. 1866.
Reprinted Garnier-Flammarion, London 1966.
3. Berry DA. When is a confirmatory randomized clinical trial needed? (editorial) Journal of the National Cancer Institute. 1996;88:1606-1607.
4. Black N. Why we need observational studies to evaluate the effectiveness of health care. British Medical Journal. 1996;312:1215-1218.
5. Bleyer WA, Tejeda HA, Murphy SB, Brawley OW, Smith MA, Ungerleider RS.
Equal participation of minority patients in U.S. national pediatric cancer clinical trials. Journal of Pediatric Hematology and Oncology. 1997;19:423-427.
6. Byar DP. Why databases should not replace randomized clinical trials.
Biometrics. 1980;36:337-342.
7. Cabana MD, Rand CS, Powe NR, Wu AW, Wilson MH, Abboud PA, Rubin HR.
Why don't physicians follow clinical practice guidelines? A framework for improvement. JAMA. 1999;282:1458-1465.
8. Califf RM, DeMets DL. Principles from clinical trials relevant to clinical practice:
Part II. Circulation. 2002;106:1172-1175.
9. Califf RM, DeMets DL. Principles from clinical trials relevant to clinical practice:
Part I. Circulation. 2002;106:1015-1021.
10. Chen J, Radford MJ, Wang Y, Marciniak TA, Krumholz HM. Do "America's Best Hospitals" perform better for acute myocardial infarction? New England Journal of Medicine. 1999;340:286-292.
11. Cochrane AL. Archie Cochrane in his own words. Selections arranged from his 1972 introduction to "Effectiveness and Efficiency: Random Reflections on the Health Services"1972. Controlled Clinical Trials. 1989;10:428-433.
12. Dans AL, Dans LF, Guyatt GH, Richardson S. Users' guides to the medical literature: XIV. How to decide on the applicability of clinical trial results to your patient. Evidence-Based Medicine Working Group. JAMA. 1998;279:545-549.
13. DeMets DL, Califf RM. Lessons learned from recent cardiovascular clinical trials:
Part II. Circulation. 2002;106:880-886.
14. DeMets DL, Califf RM. Lessons learned from recent cardiovascular clinical trials:
Part I. Circulation. 2002;106:746-751.
15. Dickersin K, Chan S, Chalmers TC, Sacks HS, Smith H Jr. Publication bias and clinical trials. Controlled Clinical Trials. 1987;8:343-853.
16. Doll R. Controlled trials: the 1948 watershed. British Medical Journal 1998;317:1217-1220.
17. Dupont WD. Randomized vs. historical clinical trials: Are the benefits worth the costs? American Journal of Epidemiology. 1985;122:940-947.
18. Easterbrook PJ, Berlin JA, Gopalan R, Matthews DR. Publication bias in clinical research. Lancet. 1991;337:867-872.
19. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. New England Journal of Medicine. 1991;324:781-788.
20. Eifel P, Axelson JA, Costa J, et al. National Institutes of Health Consensus Development Conference Statement: adjuvant therapy for breast cancer,
November 1-3, 2000. Journal of the National Cancer Institute. 2001;93:979-989.
21. Evidence-Based Medicine Working Group. Evidence-based medicine. A new approach to teaching the practice of medicine. JAMA. 1992;268:2420-2425.
22. Ferguson JH. NIH consensus conferences: Dissemination and impact. Annals of the New York Academy of Sciences. 1993;703:180-199.
23. Freedman LS, Simon R, Foulkes MA, Friedman L, Geller NL, Gordon DJ, Mowery R. Inclusion of women and minorities in clinical trials and the NIH Revitalization Act of 1993 – The perspective of NIH clinical trialists. Controlled Clinical Trials 1995;16:277-285.
24. Gamble VN. Under the shadow of Tuskegee: African Americans and health care.
American Journal of Public Health. 1997;87:1773-1778.
25. Gehan EA. The evaluation of therapies: historical control studies. Statistics in Medicine. 1984;3:315-324.
26. Gelber RD, Goldhirsch. Can a clinical trial be the treatment of choice for patients with cancer? (editorial) Journal of the National Cancer Institute. 1988;80:886-887.
27. Guidelines for the planning and management of NIH Consensus Development Conferences Online. Bethesda, MD: National Institutes of Health, Office of the Director, Office of Medical Applications of Research; 1993. updated October 2001.
28. Gunby P. Pros and cons of NIH Consensus Conferences. JAMA 1980;244:1413-1414.
29. Guyatt GH, Sinclair J, Cook DJ, Glasziou P. Users' guides to the medical literature: XVI. How to use a treatment recommendation. Evidence-Based Medicine Working Group and the Cochrane Applicability Methods Working Group. JAMA. 1999;281:1836-1843.
30. Halpern SD, Karlawish JHT, Berlin JA. The continuing unethical conduct of underpowered clinical trials. JAMA 2002;288:358-362.
31. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E.
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;280:605-613.
32. Hutchins LF, Unger JM, Crowley JJ, Coltman CA Jr, Albain KS.
Under-representation of patients 65 years of age or older in cancer-treatment trials. New England Journal of Medicine. 1999;341:2061-2067.
33. Joffe S, Weeks JC. Views of American oncologists about the purpose of clinical trials. Journal of the National Cancer Institute. 2002;94:1847-1853.
34. Kosecoff J, Kanouse DE, Rogers WH, McCloskey L, Winslow CM, Brook RH.
Effects of the National Institutes of Health Consensus Development Program on physician practice. JAMA. 1987;258:2708-2713.
35. Krzyzanowska MK, Pintilie M, Tannock IF. Factors associated with failure to publish large randomized trials presented at an oncology meeting. JAMA.
2003;290:495-501.
36. Lazovich DA, White E, Thomas DB, Moe RE. Underutilization of breast-conserving surgery and radiation therapy among women with stage I or II breast cancer. JAMA. 1991;266:3433-3438.
37. Lee PY, Alexander KP, Hammill BG, Pasquali SK, Peterson ED. Representation of elderly persons and women in published randomized trials of acute coronary syndromes. JAMA. 2001;286:708-713.
38. Levels of Evidence for Cancer Treatment Studies: Definition and Use (PDQ®).
Available from URL: http://www.nci.nih.gov/cancer_information/doc [Accessed September 5, 2002].
39. Lind JA. A Treatise on the Scurvy 1753.
40. Lomas J, Anderson GM, Domnick-Pierre K, Vayda E, Enkin MW, Hannah WJ.
Do practice guidelines guide practice? The effect of a consensus statement on the practice of physicians. New England Journal of Medicine. 1989;321:1306-1311.
41. Lukens JN. Progress resulting from clinical trials: Solid tumors in childhood cancer. Cancer. 1994;74:2710-2718.
42. Medical Research Council. Streptomycin treatment of pulmonary tuberculosis: a Medical Research Council investigation. British Medical Journal 1948;2:769-782.
43. Moertel C. Improving the efficiency of clinical trials: a medical perspective.
Statistics in Medicine. 1984;3:455-465.
44. Moher D, Schulz KF, Altman D; CONSORT Group (Consolidated Standards of Reporting Trials). The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. JAMA.
2001;285:1987-1991.
45. Moseley JB, O’Malley K, Peterson NJ, et al. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. New England Journal of Medicine.
2002;347:81-88.
46. NIH Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research. Federal Register, Part VIII (59 FR 14508-14513), March 28, 1994.
47. Oxman AD, Cook DJ, Guyatt GH. Users' guides to the medical literature. VI.
How to use an overview. Evidence-Based Medicine Working Group. JAMA.
1994;272:1367-1371.
48. Parmar MK, Ungerleider RS, Simon R. Assessing whether to perform a
confirmatory randomized clinical trial. Journal of the National Cancer Institute.
1996;88:1645-1651.
49. Packard FR. The Life and Times of Ambroise Paré, 1510-1590, New York: Paul B. Hoeber, 1921.
50. Pocock SJ. Letter to the editor 1977;1:1661.
51. Ries LAG, Eisner MP, Kosary CL, et al. (eds). SEER Cancer Statistics Review, 1975-2000, National Cancer Institute. Bethesda, MD,
http://seer.cancer.gov/csr/1975_2000, 2003.
52. Ross JA, Severson RK, Pollock BH, Robison LL. Childhood cancer in the United States: A geographical analysis of cases from the Pediatric Cooperative Clinical Trials groups. Cancer. 1996;77:201-207.
53. 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. 2002;288:321-333.
54. Royall R. Ethics and statistics in randomized clinical trials (with discussion).
Statistical Science 1991;6:52-88.
55. Sandham JD, Hull RD, Brant Rf, et al. A randomized, controlled trial of the use of pulmonary-artery catheters in high-risk surgical patients. New England Journal of Medicine. 2003;348:5-14.
56. Shavers VL, Lynch CF, Burmeister LF. Racial differences in factors that influence the willingness to participate in medical research studies. Annals of Epidemiology. 2002;12:248-256.
57. Sherman CR, Potosky AL, Weis KA, Ferguson JH. The Consensus Development Program: Detecting changes in medical practice following a Consensus
Conference on the treatment of prostate cancer. International Journal of Technology Assessment in Health Care 1992;8:683-693.
58. Smith JS. Suspended judgment. Remembering the role of Thomas Francis, Jr. in the design of the 1954 Salk Vaccine Trial. Controlled Clinical Trials
1992;13:181-184.
59. Spiegelhalter DJ, Freedman LS, Parmar MKB. Bayesian approaches to randomized clinical trials. Journal of the Royal Statistical Society Series A 1994;157:357-416.
60. Steering Committee of the Physician’s Health Study Research Group. Final report on the aspirin component of the ongoing Physician’s Health Study. New England Journal of Medicine 1989;321:129-135.
61. Stenning SP, Parmar MKB. Designing randomized trials: both large and small trials are needed. Annals of Oncology. 2002;13 Suppl 4:131-138
62. Sung NS, Crowley WF Jr, Genel M, et al. Central challenges facing the national clinical research enterprise. JAMA. 2003;289:1278-1287.
63. Tejeda HA, Green SB, Trimble EL, et al. Representation of African-Americans, Hispanics, and Whites in National Cancer Institute cancer treatment trials.
Journal of the National Cancer Institute. 1996;88:812-816.
64. 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.
65. Wortman PM, Vinokur A, Sechrest L. Do Consensus Conferences work? A process evaluation of the NIH Consensus Development Program. Journal of Health Politics, Policy, and Law 1988;13:469-497.
66. Yancik R, Ries LAG. Aging and cancer in America: demographic and
epidemiologic perspectives. Hematology Oncology Clinics of North America.
2000;14:17-23.
Level Type of Evidence
I Randomized trials with low false-positive and low false-negative errors (high power). Evidence obtained from meta-analysis of multiple well-designed, controlled studies may also be considered.
II Evidence obtained from at least one well-designed experimental study.
Randomized trials with high false-positive and/or negative errors (low power).
III Evidence obtained from well-designed, quasi-experimental studies such as non-randomized, controlled single-group, pre-post, cohort, time, or matched case-control series
IV Evidence from well-designed, nonexperimental studies such as comparative and correlative descriptive and case studies
V Evidence from case reports and clinical examples
Table 1. Typical ‘Levels of Evidence’ scheme used by National Institutes of Health to rank types of clinical studies.
Figure 1. Trends in U.S. Childhood Cancer Incidence and Mortality 1975-2000