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Current Reviews in Clinical and Experimental Pharmacology

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Review Article

Review of Clinical Equipoise: Examples from Oncology Trials

Author(s): Majd A. AlHamaly*, Karem H. Alzoubi, Omar F. Khabour, Ruba A. Jaber and Wael K. Aldelaimy

Volume 18, Issue 1, 2023

Published on: 20 January, 2022

Page: [22 - 30] Pages: 9

DOI: 10.2174/2772432817666211221164101

Price: $65

Abstract

Background: The current standards that govern clinical research have been shaped over the years through many historical, social, and political events. The third principle of the Belmont Report, Justice, guides the scientific community toward the equal distribution of benefits and risks in research involving human subjects. Clinical equipoise is the status of genuine uncertainty by the investigator about the superiority of one treatment arm over the other. The term clinical equipoise was proposed to provide an ethical ground to conduct randomized controlled clinical trials.

Objective: The objective of this review is to provide the reader with an overview of the emergence of the term equipoise and its utilization in randomized controlled trials.

Methods: In the current review article, the major oncology clinical trials and relevant patents were reviewed for the application/utilization of clinical equipoise.

Results: The concept of clinical equipoise has been challenged, and different alternatives were proposed. Yet, these alternatives received numerous critiques and failed to fully replace equipoise. In addition, several patents related to anticancer agents tested in the described studies were examined. No specific reference was made as part of the patent to the status of clinical equipoise. Alternatively, a description of the study arms was provided.

Conclusion: There is a need for revisiting the concept of equipoise and its suggested alternatives for its ethical essence while addressing related challenges.

Keywords: Ethical standards, human research, justice, patents, randomized controlled trials, equipoise.

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[1]
Artal R, Rubenfeld S. Ethical issues in research. Best Pract Res Clin Obstet Gynaecol 2017; 43: 107-14.
[http://dx.doi.org/10.1016/j.bpobgyn.2016.12.006] [PMID: 28190696]
[2]
Shuster E. Fifty years later: The significance of the Nuremberg code. N Engl J Med 1997; 337(20): 1436-40.
[http://dx.doi.org/10.1056/NEJM199711133372006] [PMID: 9358142]
[3]
White MG. Why human subjects research protection is important. Ochsner J 2020; 20(1): 16-33.
[http://dx.doi.org/10.31486/toj.20.5012] [PMID: 32284679]
[4]
Rice TW. The historical, ethical, and legal background of human- subjects research. Respir Care 2008; 53(10): 1325-9.
[PMID: 18811995]
[5]
Macrae DJ. The council for international organizations and medical sciences (CIOMS) guidelines on ethics of clinical trials. Proc Am Thorac Soc 2007; 4(2): 176-8.
[http://dx.doi.org/10.1513/pats.200701-011GC] [PMID: 17494727]
[6]
Asplund K, Hermerén G. The need to revise the Helsinki declaration. Lancet 2017; 389(10075): 1190-1.
[http://dx.doi.org/10.1016/S0140-6736(17)30776-6] [PMID: 28353437]
[7]
Sánchez López JD, Cambil Martín J, Luque Martínez F. Belmont report. A theorical and practical reviewed. J Healthc Qual Res 2021; 36(3): 179-80.
[http://dx.doi.org/10.1016/j.jhqr.2020.01.011.] [PMID: 33334699]
[8]
Department of Health, Education, and Welfare; National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont report. Ethical principles and guidelines for the protection of human subjects of research. J Am Coll Dent 2014; 81(3): 4-13.
[PMID: 25951677]
[9]
Adashi EY, Walters LB, Menikoff JA. The Belmont Report at 40: Reckoning with time. Am J Public Health 2018; 108(10): 1345-8.
[http://dx.doi.org/10.2105/AJPH.2018.304580] [PMID: 30138058]
[10]
Barrow JM, Brannan GD, Khandhar PB. Research Ethics.USA: Treasure Island (FL): StatPearls Publishing 2020.
[11]
Miracle VA. The Belmont Report: The triple crown of research ethics. Dimens Crit Care Nurs 2016; 35(4): 223-8.
[http://dx.doi.org/10.1097/DCC.0000000000000186] [PMID: 27258959]
[12]
Sackett D, Straus S, Scott Richardson W, Rosenberg W, Haynes R. Evidence-Based Medicine: How to Practice and Teach EBM. (2nd ed.), Edinburgh, London: Churchill Livingstone 2000.
[13]
Hariton E, Locascio JJ. Randomised controlled trials - the gold standard for effectiveness research: Study design: randomised controlled trials. BJOG 2018; 125(13): 1716-6.
[http://dx.doi.org/10.1111/1471-0528.15199] [PMID: 29916205]
[14]
Minneci PC, Deans KJ. Clinical trials. Semin Pediatr Surg 2018; 27(6): 332-7.
[http://dx.doi.org/10.1053/j.sempedsurg.2018.10.003] [PMID: 30473036]
[15]
Broglio K. Randomization in clinical trials: Permuted blocks and stratification. JAMA 2018; 319(21): 2223-4.
[http://dx.doi.org/10.1001/jama.2018.6360] [PMID: 29872845]
[16]
Kabisch M, Ruckes C, Seibert-Grafe M, Blettner M. Randomized controlled trials: part 17 of a series on evaluation of scientific publications. Dtsch Arztebl Int 2011; 108(39): 663-8.
[PMID: 22013494]
[17]
Spieth PM, Kubasch AS, Penzlin AI, Illigens BM, Barlinn K, Siepmann T. Randomized controlled trials - a matter of design. Neuropsychiatr Dis Treat 2016; 12: 1341-9.
[PMID: 27354804]
[18]
Rosenberger WF, Lachin JM. Randomization in clinical trials: Theory and practice. (2nd ed.), New York: John Wiley & Sons 2015.
[19]
Lim CY, In J. Randomization in clinical studies. Korean J Anesthesiol 2019; 72(3): 221-32.
[http://dx.doi.org/10.4097/kja.19049] [PMID: 30929415]
[20]
Freedman B. Equipoise and the ethics of clinical research. New England J Med 1987; 317: 141-5.
[http://dx.doi.org/10.1056/NEJM198707163170304]
[21]
Tsamaloukas AG. Central Problem is Equipoise. Dtsch Arztebl Int 2018; 115(7): 114-4.
[PMID: 29510825]
[22]
Pimple KD. Research ethics. Routledge 2017.
[http://dx.doi.org/10.4324/9781315244426]
[23]
Fried C. Medical Experimentation: Personal Integrity and Social Policy 1974. Amsterdam: North Holland 1974.
[24]
Weijer C. The ethical analysis of risk. J Law Med Ethics 2000; 28(4): 344-61.
[http://dx.doi.org/10.1111/j.1748-720X.2000.tb00686.x] [PMID: 11317427]
[25]
Lilford RJ. Equipoise is not synonymous with uncertainity. BMJ 2001; 323(7312): 574.
[http://dx.doi.org/10.1136/bmj.323.7312.574b] [PMID: 11573494]
[26]
Gifford F. Uncertainty about clinical equipoise. Clinical equipoise and the uncertainty principles both require further scrutiny. BMJ 2001; 322(7289): 795.
[http://dx.doi.org/10.1136/bmj.322.7289.795] [PMID: 11282877]
[27]
Sackett DL. Uncertainty about clinical equipoise. There is another exchange on equipoise and uncertainty. BMJ 2001; 322(7289): 795-6.
[http://dx.doi.org/10.1136/bmj.322.7289.795] [PMID: 11282879]
[28]
Yusuf S, Collins R, Peto R. Why do we need some large, simple randomized trials? Stat Med 1984; 3(4): 409-22.
[http://dx.doi.org/10.1002/sim.4780030421] [PMID: 6528136]
[29]
Peto R, Baigent C. Trials: The next 50 years: large scale randomised evidence of moderate benefits. BMJ 1998; 317(7167): 1170-1.
[http://dx.doi.org/10.1136/bmj.317.7167.1170] [PMID: 9794846]
[30]
Weijer C, Enkin MW, Shapiro SH, Glass KC. For and against: clinical equipoise and not the uncertainty principle is the moral underpinning of the randomised controlled trial. BMJ 2000; 321(7263): 756-8.
[http://dx.doi.org/10.1136/bmj.321.7263.756] [PMID: 10999914]
[31]
Sackett DL. Equipoise, a term whose time (if it ever came) has surely gone. CMAJ 2000; 163(7): 835-6.
[PMID: 11033713]
[32]
Karlawish JH, Lantos J. Community equipoise and the architecture of clinical research. Camb Q Healthc Ethics 1997; 6(4): 385-96.
[http://dx.doi.org/10.1017/S0963180100008136] [PMID: 9292216]
[33]
Djulbegovic B. The paradox of equipoise: the principle that drives and limits therapeutic discoveries in clinical research. Cancer Control 2009; 16(4): 342-7.
[http://dx.doi.org/10.1177/107327480901600409] [PMID: 19910921]
[34]
Unger JM, Cook E, Tai E, Bleyer A. The role of clinical trial participation in cancer research: barriers, evidence, and strategies. Am Soc Clin Oncol Educ Book 2016; 35: 185-98.
[http://dx.doi.org/10.1200/EDBK_156686] [PMID: 27249699]
[35]
Lau JL, Dunn MK. Therapeutic peptides: Historical perspectives, current development trends, and future directions. Bioorg Med Chem 2018; 26(10): 2700-7.
[http://dx.doi.org/10.1016/j.bmc.2017.06.052] [PMID: 28720325]
[36]
Martell RE, Sermer D, Getz K, Kaitin KI. Oncology drug development and approval of systemic anticancer therapy by the U.S. Food and Drug Administration. Oncologist 2013; 18(1): 104-11.
[http://dx.doi.org/10.1634/theoncologist.2012-0235] [PMID: 23263289]
[37]
Taylor KM, Margolese RG, Soskolne CL. Physicians’ reasons for not entering eligible patients in a randomized clinical trial of surgery for breast cancer. N Engl J Med 1984; 310(21): 1363-7.
[http://dx.doi.org/10.1056/NEJM198405243102106] [PMID: 6717508]
[38]
Benson AB III, Pregler JP, Bean JA, Rademaker AW, Eshler B, Anderson K. Oncologists’ reluctance to accrue patients onto clinical trials: An Illinois Cancer Center study. J Clin Oncol 1991; 9(11): 2067-75.
[http://dx.doi.org/10.1200/JCO.1991.9.11.2067] [PMID: 1941065]
[39]
Ellis PM. Attitudes towards and participation in randomised clinical trials in oncology: A review of the literature. Ann Oncol 2000; 11(8): 939-45.
[http://dx.doi.org/10.1023/A:1008342222205] [PMID: 11038029]
[40]
Laba JM, Senan S, Schellenberg D, et al. Identifying barriers to accrual in radiation oncology randomized trials. Curr Oncol 2017; 24(6): e524-30.
[http://dx.doi.org/10.3747/co.24.3662] [PMID: 29270062]
[41]
Cheng SK, Dietrich MS, Dilts DM. A sense of urgency: Evaluating the link between clinical trial development time and the accrual performance of cancer therapy evaluation program (NCI-CTEP) sponsored studies. Clin Cancer Res 2010; 16(22): 5557-63.
[http://dx.doi.org/10.1158/1078-0432.CCR-10-0133] [PMID: 21062929]
[42]
Tewari KS, Sill MW, Long HJ III, et al. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med 2014; 370(8): 734-43.
[http://dx.doi.org/10.1056/NEJMoa1309748] [PMID: 24552320]
[43]
Krill LS, Adelson JW, Randall LM, Bristow RE. Clinical commentary: Medical ethics and the ramifications of equipoise in clinical research. Is a confirmatory trial using a non-bevacizumab containing arm feasible in patients with recurrent cervical cancer? Gynecol Oncol 2014; 134(3): 447-9.
[http://dx.doi.org/10.1016/j.ygyno.2014.06.017] [PMID: 24976631]
[44]
Crockett AK. After equipoise: continuing research to gain FDA approval. AMA J Ethics 2015; 17(9): 839-42.
[http://dx.doi.org/10.1001/journalofethics.2015.17.9.nlit1-1509] [PMID: 26390205]
[45]
Bizzarri N, Ghirardi V, Alessandri F, et al. Bevacizumab for the treatment of cervical cancer. Expert Opin Biol Ther 2016; 16(3): 407-19.
[http://dx.doi.org/10.1517/14712598.2016.1145208] [PMID: 26796332]
[46]
Moorkens E, Vulto AG, Huys I. An overview of patents on therapeutic monoclonal antibodies in Europe: Are they a hurdle to biosimilar market entry? MAbs 2020; 12(1): 1743517.
[http://dx.doi.org/10.1080/19420862.2020.1743517] [PMID: 32306833]
[47]
Napoleone F, Kim K. Use of anti-VEGF antibodies for the treatment of cancer. EP0666868B1, 1992.
[48]
Gordon B, Chan I. Combination therapies for melanoma comprising administering cobimetinib and vemurafinib. EP2884979B1, 2012.
[49]
Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364(26): 2507-16.
[http://dx.doi.org/10.1056/NEJMoa1103782] [PMID: 21639808]
[50]
Harmon A. The New York Times. New Drugs Stir Debate on Rules of Clinical Trials. 2010. Available from: https://www.nytimes.com/2010/09/19/health/research/19trial.html
[51]
Hey SP, Truog RD. The question of clinical equipoise and patients’ best interests. AMA J Ethics 2015; 17(12): 1108-15.
[http://dx.doi.org/10.1001/journalofethics.2015.17.12.ecas1-1512] [PMID: 26698583]
[52]
Clifford S. Randomised controlled trials and tribulations. RCS Ismje 2012; 5(1): 8-11.
[53]
Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: A randomised controlled trial. Lancet 2006; 368(9544): 1329-38.
[http://dx.doi.org/10.1016/S0140-6736(06)69446-4] [PMID: 17046465]
[54]
Daugherty CK, Ratain MJ, Emanuel EJ, Farrell AT, Schilsky RL. Ethical, scientific, and regulatory perspectives regarding the use of placebos in cancer clinical trials. J Clin Oncol 2008; 26(8): 1371-8.
[http://dx.doi.org/10.1200/JCO.2007.13.5335] [PMID: 18227527]
[55]
Marcus AD. Wall Street Journal. Fighting Cancer with a Sugar Pill. 2004. 2004. Available from: https://www.wsj.com/articles/SB108666185236231341
[56]
Joffe S, Miller FG. Bench to bedside: Mapping the moral terrain of clinical research. Hastings Cent Rep 2008; 38(2): 30-42.
[http://dx.doi.org/10.1353/hcr.2008.0019] [PMID: 18457227]
[57]
Joensuu H. Sunitinib for imatinib-resistant GIST. Lancet 2006; 368(9544): 1303-4.
[http://dx.doi.org/10.1016/S0140-6736(06)69489-0] [PMID: 17046443]
[58]
Demetri GD, Reichardt P, Kang Y-K, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): An international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013; 381(9863): 295-302.
[http://dx.doi.org/10.1016/S0140-6736(12)61857-1] [PMID: 23177515]
[59]
Bharati G, Mahesh V, Bansode C, Prakash H. Novel polymorphs of sunitinib and processes for their preparation. US20110263670A1, 2008.
[60]
Michael C. Anticancer combination therapy using sunitinib malate. EP1885355A1, 2005.
[61]
Miller PB, Weijer C. Rehabilitating equipoise. Kennedy Inst Ethics J 2003; 13(2): 93-118.
[http://dx.doi.org/10.1353/ken.2003.0014] [PMID: 14569997]
[62]
Joffe S, Miller FG. Equipoise: Asking the right questions for clinical trial design. Nat Rev Clin Oncol 2012; 9(4): 230-5.
[http://dx.doi.org/10.1038/nrclinonc.2011.211] [PMID: 22231753]
[63]
Gifford F. Community-equipoise and the ethics of randomized clinical trials. Bioethics 1995; 9(2): 127-48.
[http://dx.doi.org/10.1111/j.1467-8519.1995.tb00306.x] [PMID: 11653056]
[64]
Veatch RM. The irrelevance of equipoise. J Med Philos 2007; 32(2): 167-83.
[http://dx.doi.org/10.1080/03605310701255776] [PMID: 17454421]
[65]
Miller FG, Brody H. What makes placebo-controlled trials unethical? Am J Bioeth 2002; 2(2): 3-9.
[http://dx.doi.org/10.1162/152651602317533523] [PMID: 12189059]
[66]
Miller FG, Brody H. Clinical equipoise and the incoherence of research ethics. J Med Philos 2007; 32(2): 151-65.
[http://dx.doi.org/10.1080/03605310701255750] [PMID: 17454420]
[67]
Rabinstein AA, Brinjikji W, Kallmes DF. Equipoise in clinical trials: Angst and progress. Circ Res 2016; 119(7): 798-800.
[http://dx.doi.org/10.1161/CIRCRESAHA.116.309594] [PMID: 27635084]
[68]
Glass KC, Waring D. Effective trial design need not conflict with good patient care. Am J Bioeth 2002; 2(2): 25-6.
[http://dx.doi.org/10.1162/152651602317533613] [PMID: 12189068]
[69]
Steinberg D. Clinical research should not be permitted to escape the ethical orbit of clinical care. Am J Bioeth 2002; 2(2): 27-8.
[http://dx.doi.org/10.1162/152651602317533622] [PMID: 12189069]
[70]
Lemmens T, Miller PB. Avoiding a Jekyll-and-Hyde approach to the ethics of clinical research and practice. Am J Bioeth 2002; 2(2): 14-7.
[http://dx.doi.org/10.1162/152651602317533550] [PMID: 12189062]
[71]
Weijer C. When argument fails. Am J Bioeth 2002; 2(2): 10-1.
[http://dx.doi.org/10.1162/152651602317533532] [PMID: 12189060]
[72]
Gifford F. Pulling the plug on clinical equipoise: A critique of Miller and Weijer. Kennedy Inst Ethics J 2007; 17(3): 203-26.
[http://dx.doi.org/10.1353/ken.2007.0020] [PMID: 18210981]
[73]
Menikoff J. Equipoise: beyond rehabilitation? Kennedy Inst Ethics J 2003; 13(4): 347-51.
[http://dx.doi.org/10.1353/ken.2004.0007] [PMID: 15049298]
[74]
ICH I. US Department of Health and Human Services Food and Drug Administration. E10, choice of control group and related issues in clinical trials 2001. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/e10-choice-control-group-and-related-issues-clinical-trials
[75]
Use CMPH. Reflection paper on the need for active control in therapeutic areas where use of placebo is deemed ethical and one or more established medicines are available. 2011. http://www. ema. europa. eu/docs/en_GB/document_library

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