The ethics of clinical research requires equipoise--a state of genuine uncertainty on the part of the clinical investigator regarding the comparative therapeutic merits of each arm in a trial. Should the investigator discover that one treatment is of superior therapeutic merit, he or she is ethically obliged to offer that treatment. The current understanding of this requirement, which entails that the investigator have no "treatment preference" throughout the course of the trial, presents nearly insuperable obstacles to the ethical commencement or completion of a controlled trial and may also contribute to the termination of trials because of the failure to enroll enough patients. I suggest an alternative concept of equipoise, which would be based on present or imminent controversy in the clinical community over the preferred treatment. According to this concept of "clinical equipoise," the requirement is satisfied if there is genuine uncertainty within the expert medical community--not necessarily on the part of the individual investigator--about the preferred treatment.
This article has been cited by other articles:
Terasawa, T., Dvorak, T., Ip, S., Raman, G., Lau, J., Trikalinos, T. A.
(2009). Systematic Review: Charged-Particle Radiation Therapy for Cancer. ANN INTERN MED
151: 556-565
[Abstract][Full Text]
Kowalski, C. J., Hewett, J. L.
(2009). Data and safety monitoring boards: some enduring questions.. J Law Med Ethics
37: 496-506
Ashton, C M, Wray, N P, Jarman, A F, Kolman, J M, Wenner, D M, Brody, B A
(2009). Ethics and methods in surgical trials. J. Med. Ethics
35: 579-583
[Abstract][Full Text]
Rapoport, A.
(2009). Addressing Ethical Concerns Regarding Pediatric Palliative Care Research. Arch Pediatr Adolesc Med
163: 688-691
[Full Text]
Miller, F. G.
(2009). The Randomized Controlled Trial as a Demonstration Project: An Ethical Perspective. Am. J. Psychiatry
166: 743-745
[Full Text]
Miller, F G, Joffe, S
(2009). Limits to research risks. J. Med. Ethics
35: 445-449
[Abstract][Full Text]
Barke, R.
(2009). Balancing Uncertain Risks and Benefits in Human Subjects Research. Science Technology Human Values
34: 337-364
[Abstract]
Miksad, R. A., Gonen, M., Lynch, T. J., Roberts, T. G. Jr
(2009). Interpreting Trial Results in Light of Conflicting Evidence: A Bayesian Analysis of Adjuvant Chemotherapy for Non-Small-Cell Lung Cancer. JCO
27: 2245-2252
[Abstract][Full Text]
Sargent, D.
(2009). Early Stopping for Benefit in National Cancer Institute-Sponsored Randomized Phase III Trials: The System Is Working. JCO
27: 1543-1544
[Full Text]
Watanabe, T., Sano, M., Takashima, S., Kitaya, T., Tokuda, Y., Yoshimoto, M., Kohno, N., Nakagami, K., Iwata, H., Shimozuma, K., Sonoo, H., Tsuda, H., Sakamoto, G., Ohashi, Y.
(2009). Oral Uracil and Tegafur Compared With Classic Cyclophosphamide, Methotrexate, Fluorouracil As Postoperative Chemotherapy in Patients With Node-Negative, High-Risk Breast Cancer: National Surgical Adjuvant Study for Breast Cancer 01 Trial. JCO
27: 1368-1374
[Abstract][Full Text]
Schuklenk, U., Lowry, C.
(2009). Terminal illness and access to Phase 1 experimental agents, surgeries and devices: reviewing the ethical arguments. Br Med Bull
89: 7-22
[Abstract][Full Text]
Byerly, W. G.
(2009). Working with the institutional review board. Am J Health Syst Pharm
66: 176-184
[Abstract][Full Text]
Srivastava, R., Downey, E. C., O'Gorman, M., Feola, P., Samore, M., Holubkov, R., Mundorff, M., James, B. C., Rosenbaum, P., Young, P. C., Dean, J. M.
(2009). Impact of Fundoplication Versus Gastrojejunal Feeding Tubes on Mortality and in Preventing Aspiration Pneumonia in Young Children With Neurologic Impairment Who Have Gastroesophageal Reflux Disease. Pediatrics
123: 338-345
[Abstract][Full Text]
Peppercorn, J.
(2009). Off-protocol Therapy in Oncology. Am Soc Clin Oncol Ed Book
2009: 177-181
[Abstract][Full Text]
Peppercorn, J., Burstein, H., Miller, F. G., Winer, E., Joffe, S.
(2008). Self-Reported Practices and Attitudes of US Oncologists Regarding Off-Protocol Therapy. JCO
26: 5994-6000
[Abstract][Full Text]
Van Howe, R. S., Svoboda, J. S.
(2008). Neonatal pain relief and the helsinki declaration.. J Law Med Ethics
36: 803-823
FINS, J. J.
(2008). Surgical innovation and ethical dilemmas: Precautions and proximity. Cleveland Clinic Journal of Medicine
75: S7-S12
[Full Text]
Trommelmans, L, Selling, J, Dierickx, K
(2008). Ethical reflections on clinical trials with human tissue engineered products. J. Med. Ethics
34: e1-e1
[Abstract][Full Text]
Zaslawski, C.
(2008). Ethical Considerations for Acupuncture and Chinese Herbal Medicine Clinical Trials: A Cross-cultural Perspective. Evid Based Complement Alternat Med
0: nen055v1-nen055
[Abstract][Full Text]
Parker, L. S.
(2008). The Future of Incidental Findings: Should They be Viewed as Benefits?. J Law Med Ethics
36: 341-351
Djulbegovic, B., Kumar, A., Soares, H. P., Hozo, I., Bepler, G., Clarke, M., Bennett, C. L.
(2008). Treatment Success in Cancer: New Cancer Treatment Successes Identified in Phase 3 Randomized Controlled Trials Conducted by the National Cancer Institute-Sponsored Cooperative Oncology Groups, 1955 to 2006. Arch Intern Med
168: 632-642
[Abstract][Full Text]
Daugherty, C. K., Ratain, M. J., Emanuel, E. J., Farrell, A. T., Schilsky, R. L.
(2008). Ethical, Scientific, and Regulatory Perspectives Regarding the Use of Placebos in Cancer Clinical Trials. JCO
26: 1371-1378
[Abstract][Full Text]
Amusat, N. T
(2007). On "A survey of therapeutic ultrasound..." Wong et al. Phys Ther. 2007;87:986 994.. ptjournal
87: 1558-1559
[Full Text]
Castro, M.
(2007). Placebo versus Best-Available-Therapy Control Group in Clinical Trials for Pharmacologic Therapies: Which Is Better?. Proc Am Thorac Soc
4: 570-573
[Abstract][Full Text]
Chiong, W.
(2007). Justifying Patient Risks Associated With Medical Education. JAMA
298: 1046-1048
[Full Text]
Raymond, J., Trop, I.
(2007). The Practice of Ethics in the Era of Evidence-based Radiology. Radiology
244: 643-649
[Abstract][Full Text]
Meropol, N. J.
(2007). A Renewed Call for Equipoise. JCO
25: 3392-3394
[Full Text]
Weijer, C, Miller, P B
(2007). Refuting the net risks test: a response to Wendler and Miller's "Assessing research risks systematically". J. Med. Ethics
33: 487-490
[Abstract][Full Text]
Mueller, P. S., Montori, V. M., Bassler, D., Koenig, B. A., Guyatt, G. H.
(2007). Ethical Issues in Stopping Randomized Trials Early Because of Apparent Benefit. ANN INTERN MED
146: 878-881
[Abstract][Full Text]
Vaslef, S. N., Cairns, C. B., Falletta, J. M.
(2006). Ethical and Regulatory Challenges Associated With the Exception From Informed Consent Requirements for Emergency Research: From Experimental Design to Institutional Review Board Approval. Arch Surg
141: 1019-1023
[Abstract][Full Text]
Byrne, M. M., Thompson, P.
(2006). Collective Equipoise, Disappointment, and the Therapeutic Misconception: On the Consequences of Selection for Clinical Research. Med Decis Making
26: 467-479
[Abstract]
Miller, P B, Weijer, C
(2006). Trust based obligations of the state and physician-researchers to patient-subjects.. J. Med. Ethics
32: 542-547
[Abstract][Full Text]
Allmark, P, Mason, S
(2006). Should desperate volunteers be included in randomised controlled trials?. J. Med. Ethics
32: 548-553
[Abstract][Full Text]
Tang, J.-L.
(2006). Research priorities in traditional Chinese medicine. BMJ
333: 391-394
[Full Text]
Holty, J-E C, Gould, M K
(2006). When in doubt should we cut it out? The role of surgery in non-small cell lung cancer.. Thorax
61: 554-556
[Full Text]
Miller, P. B., Weijer, C.
(2006). Fiduciary Obligation in Clinical Research. J Law Med Ethics
34: 424-440
Evans, E. L., London, A. J.
(2006). Equipoise and the Criteria for Reasonable Action. J Law Med Ethics
34: 441-450
Ridker, P. M, Torres, J.
(2006). Reported outcomes in major cardiovascular clinical trials funded by for-profit and not-for-profit organizations: 2000-2005.. JAMA
295: 2270-2274
[Abstract][Full Text]
Buchanan, D. R., Miller, F. G.
(2006). Justice and Fairness in the Kennedy Krieger Institute Lead Paint Study: the Ethics of Public Health Research on Less Expensive, Less Effective Interventions. AJPH
96: 781-787
[Abstract][Full Text]
Kraemer, H. C., Mintz, J., Noda, A., Tinklenberg, J., Yesavage, J. A.
(2006). Caution Regarding the Use of Pilot Studies to Guide Power Calculations for Study Proposals.. Arch Gen Psychiatry
63: 484-489
[Abstract][Full Text]
Gatchel, R. J., Stowell, A. W., Wildenstein, L., Riggs, R., Ellis, E. III
(2006). Efficacy of an early intervention for patients with acute temporomandibular disorder-related pain: A one-year outcome study. Journal of the American Dental Association
137: 339-347
[Abstract][Full Text]
Nagasako, E. M., Kalauokalani, D. A.
(2005). Ethical aspects of placebo groups in pain trials: Lessons from psychiatry. Neurology
65: S59-S65
[Abstract][Full Text]
Kumar, A., Soares, H., Wells, R., Clarke, M., Hozo, I., Bleyer, A., Reaman, G., Chalmers, I., Djulbegovic, B.
(2005). Are experimental treatments for cancer in children superior to established treatments? Observational study of randomised controlled trials by the Children's Oncology Group. BMJ
331: 1295-
[Abstract][Full Text]
Holdsworth, M. T, Vo-Nguyen, T.
(2005). Employment of Substandard Antiemetic Prophylaxis in Recent Trials of Chemotherapy-Induced Nausea and Vomiting. The Annals of Pharmacotherapy
39: 1903-1910
[Abstract][Full Text]
Botkin, J. R.
(2005). Research for Newborn Screening: Developing a National Framework. Pediatrics
116: 862-871
[Abstract][Full Text]
Glass, K. C., Waring, D.
(2005). The Physician/Investigator's Obligation to Patients Participating in Research: The Case of Placebo Controlled Trials. J Law Med Ethics
33: 575-585
Morreim, E. H.
(2005). The Clinical Investigator as Fiduciary: Discarding a Misguided Idea. J Law Med Ethics
33: 586-598
Mann, H
(2005). Controversial choice of a control intervention in a trial of ventilator therapy in ARDS: standard of care arguments in a randomised controlled trial. J. Med. Ethics
31: 548-553
[Abstract][Full Text]
Anderson, R. M.
(2005). Is It Ethical to Assign Medically Underserved African Americans to a Usual-Care Control Group in Community-Based Intervention Research?. Diabetes Care
28: 1817-1820
[Full Text]
Fergusson, D., Glass, K. C., Hutton, B., Shapiro, S.
(2005). Randomized controlled trials of aprotinin in cardiac surgery: could clinical equipoise have stopped the bleeding?. Clin Trials
2: 218-232
[Abstract]
Mann, H., London, A. J., Mann, J.
(2005). Equipoise in the Enhanced Supression of the Platelet IIb/IIIa Receptor with Integrilin Trial (ESPRIT): a critical appraisal. Clin Trials
2: 233-243
[Abstract]
Heilig, C. M, Weijerb, C.
(2005). A critical history of individual and collective ethics in the lineage of Lellouch and Schwartz. Clin Trials
2: 244-253
[Abstract]
Jackson, W. L. Jr
(2005). Should We Use Etomidate as an Induction Agent for Endotracheal Intubation in Patients With Septic Shock?: A Critical Appraisal. Chest
127: 1031-1038
[Abstract][Full Text]
Soares, H. P., Kumar, A., Daniels, S., Swann, S., Cantor, A., Hozo, I., Clark, M., Serdarevic, F., Gwede, C., Trotti, A., Djulbegovic, B.
(2005). Evaluation of New Treatments in Radiation Oncology: Are They Better Than Standard Treatments?. JAMA
293: 970-978
[Abstract][Full Text]
Heckerling, P. S.
(2005). Treating Controls in Unblinded Trials. ANN INTERN MED
142: 309-309
[Full Text]
Miller, A
(2005). Ethical Issues in MS Clinical Trials. Mult Scler
11: 97-98
(2004). The Ethical Conduct of Clinical Research Involving Critically Ill Patients in the United States and Canada: Principles and Recommendations. Am. J. Respir. Crit. Care Med.
170: 1375-1384
[Full Text]
McLeod, D
(2004). Is it time to call time on the scleral buckle?. Br J Ophthalmol
88: 1357-1359
[Full Text]
Brenner, M., Hanna, N. M., Mina-Araghi, R., Gelb, A. F., McKenna, R. J. Jr, Colt, H.
(2004). Innovative Approaches to Lung Volume Reduction for Emphysema. Chest
126: 238-248
[Abstract][Full Text]
Stamm, J.W.
(2004). The Classic Caries Clinical Trial: Constraints and Opportunities. JDR
83: C6-C14
[Full Text]
Joffe, S., Harrington, D. P, George, S. L, Emanuel, E. J, Budzinski, L. A, Weeks, J. C
(2004). Satisfaction of the uncertainty principle in cancer clinical trials: retrospective cohort analysis. BMJ
328: 1463-
[Abstract][Full Text]
Diamond, G. A., Kaul, S.
(2004). Prior convictions: bayesian approaches to the analysis and interpretation of clinical megatrials. J Am Coll Cardiol
43: 1929-1939
[Abstract][Full Text]
Wendler, D., Emanuel, E. J., Lie, R. K.
(2004). The Standard of Care Debate: Can Research in Developing Countries Be Both Ethical and Responsive to Those Countries' Health Needs?. AJPH
94: 923-928
[Abstract][Full Text]
Kent, D. M., Fendrick, A. M., Langa, K. M.
(2004). New and Dis-Improved: On the Evaluation and Use of Less Effective, Less Expensive Medical Interventions. Med Decis Making
24: 281-286
[Abstract]
Lader, E. W., Cannon, C. P., Ohman, E. M., Newby, L. K., Sulmasy, D. P., Barst, R. J., Fair, J. M., Flather, M., Freedman, J. E., Frye, R. L., Hand, M. M., Jesse, R. L., Van de Werf, F., Costa, F.
(2004). The Clinician as Investigator: Participating in Clinical Trials in the Practice Setting. Circulation
109: 2672-2679
[Abstract][Full Text]
Garcia, J., Elbourne, D., Snowdon, C.
(2004). Equipoise: a case study of the views of clinicians involved in two neonatal trials. Clin Trials
1: 170-178
[Abstract]
Evans, H M
(2004). Should patients be allowed to veto their participation in clinical research?. J. Med. Ethics
30: 198-203
[Abstract][Full Text]
Krouse, R. S., Rosenfeld, K. E., Grant, M., Aziz, N., Byock, I., Sloan, J., Casarett, D.
(2004). Palliative Care Research: Issues and Opportunities. Cancer Epidemiol. Biomarkers Prev.
13: 337-339
[Full Text]
Miller, F. G., Silverman, H. J.
(2004). The Ethical Relevance of the Standard of Care in the Design of Clinical Trials. Am. J. Respir. Crit. Care Med.
169: 562-564
[Full Text]
Lynn, J
(2004). When does quality improvement count as research? Human subject protection and theories of knowledge. Qual Saf Health Care
13: 67-70
[Abstract][Full Text]
Kerr, C, Robinson, E, Stevens, A, Braunholtz, D, Edwards, S, Lilford, R
(2004). Randomisation in trials: do potential trial participants understand it and find it acceptable?. J. Med. Ethics
30: 80-84
[Abstract][Full Text]
Thomson, H., Hoskins, R., Petticrew, M., Ogilvie, D., Craig, N., Quinn, T., Lindsay, G.
(2004). Evaluating the health effects of social interventions. BMJ
328: 282-285
[Full Text]
Kodish, E., Eder, M., Noll, R. B., Ruccione, K., Lange, B., Angiolillo, A., Pentz, R., Zyzanski, S., Siminoff, L. A., Drotar, D.
(2004). Communication of Randomization in Childhood Leukemia Trials. JAMA
291: 470-475
[Abstract][Full Text]
Sabin, J. E., Daniels, N.
(2004). Managed Care: Improving Psychiatric Drug Benefit Management: III. The VA's Approach to Atypical Antipsychotics. Psychiatr. Serv.
55: 22-25
[Full Text]
Silverman, H. J., Luce, J. M., Schwartz, J.
(2004). Protecting Subjects with Decisional Impairment in Research: The Need for a Multifaceted Approach. Am. J. Respir. Crit. Care Med.
169: 10-14
[Full Text]
Coffey, M. J., Wilfond, B., Ross, L. F.
(2004). Ethical Assessment of Clinical Asthma Trials Including Children Subjects. Pediatrics
113: 87-94
[Abstract][Full Text]
Kappos, L, Polman, C, Thompson, A J, Duda, P, Clanet, M, Comi, G, Hartung, H P, Montalban, X
(2003). Towards a European Network for Multiple Sclerosis Trials (ENMST). Mult Scler
9: 627-629
[Abstract]
Clark, W. F., Garg, A. X., Blake, P. G., Rock, G. A., Heidenheim, A. P., Sackett, D. L.
(2003). Effect of Awareness of a Randomized Controlled Trial on Use of Experimental Therapy. JAMA
290: 1351-1355
[Abstract][Full Text]
Whitney, S. N.
(2003). A New Model of Medical Decisions: Exploring the Limits of Shared Decision Making. Med Decis Making
23: 275-280
[Abstract]
Boozang, K. M.
(2003). National Policy on CAM: The White House Commission Report. J Law Med Ethics
31: 251-261
Chen, D. T., Miller, F. G., Rosenstein, D. L.
(2003). Clinical Research and the Physician-Patient Relationship. ANN INTERN MED
138: 669-672
[Abstract][Full Text]
Miller, F. G., Rosenstein, D. L.
(2003). The Therapeutic Orientation to Clinical Trials. NEJM
348: 1383-1386
[Full Text]
Grunberg, S. M., Cefalu, W. T.
(2003). The Integral Role of Clinical Research in Clinical Care. NEJM
348: 1386-1388
[Full Text]
Karlawish, J. H.T.
(2003). Research Involving Cognitively Impaired Adults. NEJM
348: 1389-1392
[Full Text]
Mann, H., Djulbegovic, B., Gold, P.
(2003). Letter to the Editor. J Law Med Ethics
31: 5-6
Carpenter, W. T. Jr., Appelbaum, P. S., Levine, R. J.
(2003). The Declaration of Helsinki and Clinical Trials: A Focus on Placebo-Controlled Trials in Schizophrenia. Am. J. Psychiatry
160: 356-362
[Abstract][Full Text]
Jubb, A M
(2002). Palliative care research: trading ethics for an evidence base. J. Med. Ethics
28: 342-346
[Abstract][Full Text]
McKeown, R E, Weed, D L
(2002). Ethics in epidemiology and public health II. Applied terms. J. Epidemiol. Community Health
56: 739-741
[Abstract][Full Text]
Senn, S
(2002). Ethical considerations concerning treatment allocation in drug development trials. Stat Methods Med Res
11: 403-411
[Abstract]
London, A. J., Kadane, J. B.
(2002). Placebos that harm: sham surgery controls in clinical trials. Stat Methods Med Res
11: 413-427
[Abstract]
Johnston, L. E. Jr.
(2002). Moving forward by looking back: 'Retrospective' clinical studies. J. Orthod.
29: 221-226
[Full Text]
Wible, J. R., Dietrich, S.
(2002). Innovative Therapies, Suspended Trials, and the Economics of Clinical Research: Facilitated Communication and Biomedical Cases. Philosophy of the Social Sciences
32: 275-309
[Abstract]
Ellis, P. M., Butow, P. N., Tattersall, M. H. N.
(2002). Informing breast cancer patients about clinical trials: a randomized clinical trial of an educational booklet. Ann Oncol
13: 1414-1423
[Abstract][Full Text]
Rao, J. N, Cassia, L J S.
(2002). Ethics of undisclosed payments to doctors recruiting patients in clinical trials. BMJ
325: 36-37
[Full Text]
Fung, E. K., Lore, J. M.
(2002). Randomized Controlled Trials for Evaluating Surgical Questions. Arch Otolaryngol Head Neck Surg
128: 631-634
[Abstract][Full Text]
Clark, P. A.
(2002). Placebo Surgery for Parkinson's Disease: Do the Benefits Outweigh the Risks?. J Law Med Ethics
30: 58-68
Weijer, C.
(2002). Placebo trials and tribulations. CMAJ
166: 603-604
[Full Text]
Previous
