Abstract
People have debated the ethics of clinical trials for as long as trials have been conducted. The arguments have changed over the years and perhaps become more sophisticated, but many of them involve issues such as the physician’s obligations to the individual patient versus societal good; clinical equipoise; study design considerations such as randomization and the choice of control group, including use of placebo; informed consent; conduct of trials in underdeveloped areas and world regions; conflicts of interest; participant confidentiality and sharing of data and specimens; lack of publication; and publication bias.
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Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA 2000;283:2701-11.
Emanuel EJ, Grady C, Crouch RA, et al (eds.). The Oxford Textbook of Clinical Research Ethics. Oxford: Oxford University Press, 2008.
U.S. Department of Health & Human Services website. The Nuremberg Code. Available at: http://www.hhs.gov/ohrp/archive/nurcode.html. Accessed January 14, 2015.
World Medical Association website. WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects. Available at: http://www.wma.net/en/30publications/10policies/b3/index.html. Accessed January 14, 2015.
U.S. Department of Health & Human Services website. The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. April 18, 1979. Available at: http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html. Accessed January 14, 2015.
Council for International Organizations of Medical Sciences, World Health Organization. International Ethical Guidelines for Biomedical Research Involving Human Subjects. Available at: http://www.cioms.ch/publications/layout_guide2002.pdf. Accessed January 14, 2015.
National Institutes of Health Clinical Center, U.S. Department of Health & Human Services. Ethics in Clinical Research. Available at: http://clinicalcenter.nih.gov/recruit/ethics.html. Accessed January 14, 2015.
National Institutes of Health Clinical Center, U.S. Department of Health & Human Services. Clinical Research Training On-Line. Available at: http://cc.nih.gov/training/training/crt.html. Accessed January 14, 2015.
National Institutes of Health Clinical Center, U.S. Department of Health & Human Services. Ethical and Regulatory Aspects of Clinical Research. Available at: http://www.bioethics.nih.gov/courses/index.shtml. Accessed January 14, 2015.
Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. N Engl J Med 1989;321:406-412.
Elliott C. Guinea-pigging: healthy human subjects for drug safety trials are in demand. But is it a living? New Yorker 2008;7:36-41.
Jonsen AR, Miller FG. Research with healthy volunteers. In: Emanuel EJ, Grady C, Crouch RA, et al (eds.). The Oxford Textbook of Clinical Research Ethics. Oxford: Oxford University Press, 2008:481-487.
Dickert N, Grady C. Incentives for research participants. In: Emanuel EJ, Grady C, Crouch RA, et al (eds.). The Oxford Textbook of Clinical Research Ethics. Oxford: Oxford University Press, 2008:386-396.
Savulescu J, Spriggs M. The hexamethonium asthma study and the death of a normal volunteer in research. J Med Ethics 2002;28:3-4.
Suntharalingam G, Perry MR, Ward S, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 2006;355:1018-1028.
St Clair EW. The calm after the cytokine storm: lessons from the TGN1412 trial. J Clin Invest 2008;118:1344-1347 (correction J Clin Invest 2008;118:2365).
Agrawal M, Emanuel EJ. Ethics of phase 1 oncology studies: reexamining the arguments and data. JAMA 2003;290:1075-1082.
Joffe S, Miller FG. Bench to bedside: mapping the moral terrain of clinical research. Hastings Cent Rep 2008;38:30-42.
Tricoci P, Allen JM, Kramer JM, et al. Scientific evidence underlying the ACC/AHA clinical practice guidelines. JAMA 2009;301:831-841.
Patient-Centered Outcomes Research Institute website. Available at: http://www.pcori.org/. Accessed January 14, 2015.
SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network, Carlo WA, Finer NN, et al. Target ranges of oxygen saturation in extremely preterm infants. N Engl J Med 2010;362:1959-1969.
Human Research Protections under Federalwide Assurance (FWA) 5960. http://www.hhs.gov/ohrp/detrm_letrs/YR13/mar13a.pdf. Accessed January 14, 2015.
Lantos JD. The weird divergence of ethics and regulation with regard to informed consent. Am J Bioeth 2013;13:31-33.
Lantos JD, Spertus JA. The concept of risk in comparative-effectiveness research. N Engl J Med 2014;371:2129-2130.
Research America: An Alliance for Discoveries in Health. Research Enterprise Survey, February 2010 (slide presentation). Available at: http://www.researchamerica.org/uploads/ResearchEnterprisePoll.pdf. Accessed January 14, 2015.
Schaefer GO, Emanuel EJ, Wertheimer A. The obligation to participate in biomedical research. JAMA 2009;302:67-72.
Califf RM, Zarin DA, Kramer JM, et al. Characteristics of clinical trials registered in ClinicalTrials.gov, 2007-2010. JAMA 2012;307:1838-1847
Freedman B. Equipoise and the ethics of clinical research. N Engl J Med 1987;317:141-145.
Shaw LW, Chalmers TC. Ethics in cooperative clinical trials. Ann N Y Acad Sci 1970;169:487-495.
Byar DP, Simon RM, Friedewald WT, et al. Randomized clinical trials. Perspectives on some recent ideas. N Engl J Med 1976;295:74-80.
Spodick DH. The randomized controlled clinical trial. Scientific and ethical bases. Am J Med 1982;73:420-425.
Royall RM, Bartlett RH, Cornell RG, et al. Ethics and statistics in randomized clinical trials. Stat Sci 1991;6:52-88.
Intravenous streptokinase given within 0-4 hours of onset of myocardial infarction reduced mortality in ISIS-2. Lancet 1987;1:502.
Huang SS, Septimus E, Kleinman K, et al. Targeted versus universal decolonization to prevent ICU infection. N Engl J Med 2013;368:2255-2265.
Dawson L, Zarin DA, Emanuel EJ, et al. Considering usual medical care in clinical trial design. PLoS Med 2009;6:e1000111.
Holm S, Harris J. The standard of care in multinational research. In: Emanuel EJ, Grady C, Crouch RA, et al (eds.). The Oxford Textbook of Clinical Research Ethics. Oxford: Oxford University Press, 2008:729-736.
Bhatt DL, Kandzari DE, O’Neill WW, et al.; SYMPLICITY HTN-3 Investigators. A controlled trial of renal denervation for resistant hypertension. N Engl J Med 2014;370:1393-1401.
Temple RJ, Meyer R. Continued need for placebo in many cases, even when there is effective therapy. Arch Intern Med 2003;163:371-373.
Freedman B, Weijer C, Glass KC. Placebo orthodoxy in clinical research. I: Empirical and methodological myths. J Law Med Ethics 1996;24:243-251.
Freedman B, Glass KC, Weijer C. Placebo orthodoxy in clinical research. II: Ethical, legal, and regulatory myths. J Law Med Ethics 1996;24:252-259.
Rothman KJ, Michels KB. The continuing unethical use of placebo controls. N Engl J Med 1994;331:394-398.
Michels KB, Rothman KJ. Update on unethical use of placebos in randomised trials. Bioethics 2003;17:188-204.
O’Shea JC, Hafley GE, Greenberg S, et al. Platelet glycoprotein IIb/IIIa integrin blockade with eptifibatide in coronary stent intervention: the ESPRIT trial: a randomized controlled trial. JAMA 2001;285:2468-2473.
Mann H, London AJ, Mann J. Equipoise in the enhanced suppression of the platelet IIb/IIIa receptor with integrilin trial (ESPRIT): a critical appraisal. Clin Trials 2005;2:233-241.
Tcheng J. Comment on Mann et al. Clin Trials 2005;2:242-243.
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use: ICH Harmonised Tripartite Guideline: Choice of Control Group and Related Issues in Clinical Trials E10 (July 2000). http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E10/Step4/E10_Guideline.pdf
Miller FG. The ethics of placebo-controlled trials. In: Emanuel EJ, Grady C, Crouch RA, et al (eds.). The Oxford Textbook of Clinical Research Ethics. Oxford: Oxford University Press, 2008:261-272.
Levinsky NG. Nonfinancial conflicts of interest in research. N Engl J Med 2002;347:759-761.
Weinfurt KP, Hall MA, King NM, et al. Disclosure of financial relationships to participants in clinical research. N Engl J Med 2009;361:916-921.
Code of Federal Regulations, Title 45, Part 46. Available at: http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html. Accessed January 14, 2015.
Code of Federal Regulations, Title 21. Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm. Accessed January 14, 2015.
Code of Federal Regulations, Title 21, Part 50. Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=50. Accessed January 14, 2015.
Cassileth BR, Zupkis RV, Sutton-Smith K, et al. Informed consent -- why are its goals imperfectly realized? N Engl J Med 1980;302:896-900.
Grunder TM. On the readability of surgical consent forms. N Engl J Med 1980;302:900-902.
Howard JM, DeMets D. How informed is informed consent? The BHAT experience. Control Clin Trials 1981;2:287-303.
Henderson GE, Churchill LR, Davis AM, et al. Clinical trials and medical care: defining the therapeutic misconception. PLoS Med 2007;4:e324.
U.S. Food and Drug Administration. Exception from informed consent requirements for emergency research. Available at: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM249673.pdf. Accessed January 14, 2015.
Federal Register, volume 61, October 2, 1996. 45 CFR Part 46, pages 5131–3; Department of Health & Human Services, Waiver of Informed Consent Requirements in Certain Emergency Research. Available at: http://www.hhs.gov/ohrp/policy/hsdc97-01.html. Accessed January 14, 2015.
Tri-Council Policy Statement: Ethical conduct for research involving humans (amended 2005). http://www.ncehr-cnerh.org/english/code_2/. Accessed January 14, 2015.
European Medicines Agency ICH Topic E6 (R1) Guideline for Good Clinical Practice, January 1997 (corrected July 2002). Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002874.pdf. Accessed January 14, 2015.
Bottiger BW, Arntz HR, Chamberlain DA, et al. Thrombolysis during resuscitation for out-of-hospital cardiac arrest. N Engl J Med 2008;359:2651-2662.
Kim F, Nichol G, Maynard C, et al. Effect of prehospital induction of mild hypothermia on survival and neurological status among adults with cardiac arrest: a randomized clinical trial. JAMA 2014;311:45-52.
Burton TM. Despite heart attack deaths, PolyHeme still being tested on trauma patients. Wall Street Journal February 22, 2006.
Kipnis K, King NM, Nelson RM. Trials and errors: barriers to oversight of research conducted under the emergency research consent waiver. IRB 2006;28:16-19.
Kim SY, Miller FG. Informed consent for pragmatic trials--the integrated consent model. N Engl J Med 2014;370:769-772.
U.S. Department of Health & Human Services. Frequently Asked Questions About Human Research. Available at: http://answers.hhs.gov/ohrp/categories/1568. Accessed January 14, 2015.
Karlawish JH. Research involving cognitively impaired adults. N Engl J Med 2003;348:1389-1392.
Rosenstein DL, Miller FG. Research involving those at risk for impaired decision-making capacity. In: Emanuel EJ, Grady C, Crouch RA, et al (eds.). The Oxford Textbook of Clinical Research Ethics. Oxford: Oxford University Press, 2008:437-445.
Steinbrook R. How best to ventilate? Trial design and patient safety in studies of the acute respiratory distress syndrome. N Engl J Med 2003;348:1393-1401.
Silverman HJ, Luce JM, Schwartz J. Protecting subjects with decisional impairment in research: the need for a multifaceted approach. Am J Respir Crit Care Med 2004;169:10-14.
Glickman SW, McHutchison JG, Peterson ED, et al. Ethical and scientific implications of the globalization of clinical research. N Engl J Med 2009;360:816-823.
Love RR, Duc NB, Allred DC, et al. Oophorectomy and tamoxifen adjuvant therapy in premenopausal Vietnamese and Chinese women with operable breast cancer. J Clin Oncol 2002;20:2559-2566.
Orlandini A, Díaz R, Wojdyla D, et al. Outcomes of patients in clinical trials with ST-segment elevation myocardial infarction among countries with different gross national incomes. Eur Heart J 2006;27:527-533.
Vickers A, Goyal N, Harland R, et al. Do certain countries produce only positive results? A systematic review of controlled trials. Control Clin Trials 1998;19:159-166.
O’Shea JC, Califf RM. International differences in cardiovascular clinical trials. Am Heart J 2001;141:875-880.
London AL. Responsiveness to host community health needs. In: Emanuel EJ, Grady C, Crouch RA, et al (eds.). The Oxford Textbook of Clinical Research Ethics. Oxford: Oxford University Press, 2008:737-744.
Lind SE. Finder’s fees for research subjects. N Engl J Med 1990;323:192-195.
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 1994;330:1029-1035.
Miller AB, Buring J, Williams OD. Stopping the Carotene and Retinol Efficacy Trial: The Viewpoint of the Safety and Endpoint Monitoring Committee. In: DeMets DL, Furberg CD, Friedman LM (eds.). Data Monitoring in Clinical Trials: A Case Studies Approach. New York: Springer, 2006: 220-227.
Age-Related Eye Disease Study Research Group. The Age-Related Eye Disease Study (AREDS): design implications. AREDS report no. 1. Control Clin Trials 1999;20:573-600.
Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol 2001;119:1417-1436
Tegeler CH, Furberg CD. Lessons from warfarin trials in atrial fibrillation: missing the window of opportunity. In: DeMets DL, Furberg CD, Friedman LM (eds.). Data Monitoring in Clinical Trials: A Case Studies Approach. New York: Springer, 2006:312-319.
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 1998;280:605-613.
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.
Hulley SB, Grady D, Vittinghoff E, et al. Consideration of early stopping and other challenges in monitoring the Heart and Estrogen/Progestin Replacement Study. In: DeMets DL, Furberg CD, Friedman LM (eds.). Data Monitoring in Clinical Trials: A Case Studies Approach. New York: Springer, 2006:236-247.
Wittes J, Barrett-Connor E, Braunwald E, et al. Monitoring the randomized trials of the Women’s Health Initiative: the experience of the Data and Safety Monitoring Board. Clin Trials 2007;4:218-234.
Peppercorn J, Buss WG, Fost N, et al. The dilemma of data-safety monitoring: provision of significant new data to research participants. Lancet 2008;371:527-529.
Black HR, Elliott WJ, Grandits G, et al. Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial. JAMA 2003;289:2073-2082.
Psaty BM, Rennie D. Stopping medical research to save money: a broken pact with researchers and patients. JAMA 2003;289: 2128-2131.
Marcus AD. Paying to keep your drug trial alive. Wall Street Journal. April 10, 2007.
National Institutes of Health, U.S. Department of Health & Human Services. Health Insurance Portability and Accountability Act (HIPAA). Available at: http://privacyruleandresearch.nih.gov/. Accessed January 14, 2015.
National Institutes of Health, U.S. Department of Health & Human Services. NIH Data Sharing Policy and Implementation Guidance (updated March 5, 2003). Available at: http://grants.nih.gov/grants/policy/data_sharing/data_sharing_guidance.htm. Accessed January 14, 2015.
Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies (GWAS). Available at: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-088.html. Accessed January 14, 2015.
Zarin DA, Tse T. Medicine. Moving toward transparency of clinical trials. Science 2008;319:1340-1342.
Wilson D, Meier B. Doctor falsified study on injured G.I.’s, Army says. The New York Times. May 12, 2009.
Scott J. Withdrawal of a paper. J Bone Joint Surg Br 2009;91:285-286.
Fisher B, Anderson S, Redmond CK, et al. Reanalysis and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1995;333:1456-1461.
Angell M, Kassirer JP. Setting the record straight in the breast cancer trials. N Engl J Med 1994;330:1448-1450.
Turner EH, Matthews AM, Linardatos E, et al. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 2008;358:252-260.
Heres S, Davis J, Maino K, et al. Why olanzapine beats risperidone, risperidone beats quetiapine, and quetiapine beats olanzapine: an exploratory analysis of head-to-head comparison studies of second-generation antipsychotics. Am J Psychiatry 2006;163:185-194.
Packer M, Carson P, Elkayam U, et al. Effect of amlodipine on the survival of patients with severe chronic heart failure due to a nonischemic cardiomyopathy: results of the PRAISE-2 study (prospective randomized amlodipine survival evaluation 2). JACC Heart Fail 2013;1:308-314.
Pfeffer MA, Skali H. PRAISE (prospective randomized amlodipine survival evaluation) and criticism. JACC Heart Fail 2013;1:315-317.
International Committee of Medical Journal Editors. Uniform requirements for manuscripts submitted to biomedical journals: writing and editing for biomedical publication (updated October 2008). Available at: http://www.icmje.org/. Accessed January 14, 2015.
Clinical Trials Registration in ClinicalTrials.gov (Public Law 110-85): Competing Applications and Non-Competing Progress Reports. Available at: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-023.html. Accessed January 14, 2015.
Federal Register, volume 73, Number 99, May 21, 2008. Available at: http://edocket.access.gpo.gov/2008/E8-11042.htm. Accessed January 14, 2015.
Zarin DA, Tse T, Williams RJ, et al. The ClinicalTrials.gov results database--update and key issues. N Engl J Med 2011;364:852-860.
Steinbrook R. Gag clauses in clinical-trial agreements. N Engl J Med 2005;352:2160-2162.
Drazen JM, Van Der Weyden MB, Sahni P, et al. Uniform format for disclosure of competing interests in ICMJE journals. N Engl J Med 2009;361:1896-1897.
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Friedman, L.M., Furberg, C.D., DeMets, D.L., Reboussin, D.M., Granger, C.B. (2015). Ethical Issues. In: Fundamentals of Clinical Trials. Springer, Cham. https://doi.org/10.1007/978-3-319-18539-2_2
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