Ethics and Uncertainty: Considerations for the Design and Review of Translational Trials Involving Stem Cells

  • James A. Anderson
  • Jonathan Kimmelman
Part of the Stem Cell Biology and Regenerative Medicine book series (STEMCELL)


Once we set aside issues related to the ontological status of the human embryo, many of the ethical issues presented by translational stem cell trials resemble those presented by other areas of clinical research. Does the trial present a favorable balance of risks and benefits? Will the selection of subjects be fair? Will the consent of participants be informed and voluntary? The familiarity of these questions, however, belies difficulties faced by researchers and regulators involved in the design and review of translational stem cell trials. In this context, issues are problematized by high degrees of uncertainty concerning the nature and probability of study risks, the absence of accepted normative standards or frameworks for risk assessment, and the limited expertise concerning stem cell science on most institutional review committees.


Phase 1 Research ethics Risk Stem cells Translational research 


  1. 1.
    Friedmann T. Lessons for the stem cell discourse from the gene therapy experience. Perspect Biol Med 2005; 48:585–91.PubMedCrossRefGoogle Scholar
  2. 2.
    Kimmelman J. Gene transfer and the ethics of first-in-human research: Lost in Translation. Cambridge: Cambridge University Press; 2010.Google Scholar
  3. 3.
    Kimmelman J. Tomorrow, interrupted? Risk, ethics, and medical advance in gene transfer. Mol Ther 2009; 17:1838–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Wilson JM. Medicine. A history lesson for stem cells. Science 2009; 324:727–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Kimmelman J, London AJ, Ravina B, Ramsay T, Bernstein M, Fine A, et al. Launching invasive, first-in-human trials against Parkinson’s disease: Ethical considerations. Mov Disord 2009; 24:1893–901.PubMedCrossRefGoogle Scholar
  6. 6.
    Kimmelman J. Ethics at phase 0: Clarifying the issues. J Law Med Ethics 2007 Winter; 35:727–33.Google Scholar
  7. 7.
    Association of American Medical Colleges. Promoting Translational and Clinical Science: The Critical Role of Medical Schools and Teaching Hospitals. Report of the AAMC’s Task Force II on Clinical Research; 2006.Google Scholar
  8. 8.
    Food and Drug Administration. FDA Guidance for Industry, Draft Guidance, INDs – Approaches to Complying with CGMP During Phase 1; 2006.Google Scholar
  9. 9.
    Food and Drug Administration. Critical Path Report, Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products; 2004.Google Scholar
  10. 10.
    Zerhouni E. The NIH roadmap. Science 2003; 302:63–72.PubMedCrossRefGoogle Scholar
  11. 11.
    Lehmann F, Lacombe D, Therasse P, Eggermont AM. Integration of translational research in the European Organisation for Research and Treatment of Cancer Research (EORTC) clinical trial cooperative group mechanisms. J Transl Med 2003; 1:2.PubMedCrossRefGoogle Scholar
  12. 12.
    Rowett L. UK Initiative to boost translational research. J Natl Cancer Inst 2002; 94: 715–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Miller F, Joffe S. Limits to research risks. J Med Ethics 2009; 35:445–9.PubMedCrossRefGoogle Scholar
  14. 14.
    London, AJ. Does research ethics rest on a mistake? The common good, reasonable risk and social justice. Am J Bioeth 2005; 5:37–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Kimmelman, J. Valuing risk: The ethical review of clinical trial safety. Kennedy Inst Ethics J 2004; 14:369–93.PubMedCrossRefGoogle Scholar
  16. 16.
    Matthews DJ, Sugarman J, Bok H, Blass DM, Coyle JT, Duggan P et al. Cell-Based interventions for neurologic conditions: Ethical challenges for early human trials. Neurology 2008; 71:288–93.CrossRefGoogle Scholar
  17. 17.
    National Bioethics Advisory Commission. Ethical and Policy Issues in International Research: Clinical Trials in Developing Countries. Bethesda, Maryland: National Bioethics Advisory Commission; 2001.Google Scholar
  18. 18.
    Kimmelman J. Recent developments in gene transfer: Risk and ethics. BMJ 2005; 330:79–82.PubMedCrossRefGoogle Scholar
  19. 19.
    Lo B, Parham L. Ethical issues in stem cell research. Endocr Rev 2009; 30:204–13.PubMedCrossRefGoogle Scholar
  20. 20.
    Lo B, Kriegstein A, Grady D. Clinical trials in stem cell transplantation: Guidelines for scientific and ethical review. Clin Trials 2008; 5:517–22.PubMedCrossRefGoogle Scholar
  21. 21.
    Kaufmann DS. Toward clinical therapies using hematopoietic cells derived from human pluripotent stem cells. Blood 2005; 114:3513–23.CrossRefGoogle Scholar
  22. 22.
    Hyun I, Lindvall O, Ahrlund-Richter L, Cattaneo E, Cavazzana-Calvo M, Cossu G, et al. New ISSCR guidelines underscore major principles for responsible translational stem cell research. Cell Stem Cell 2008; 3:607–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Li JY, Christophersen NS, Hall V, Soulet D, Brundin P. Critical issues of clinical human embryonic stem cell therapy for brain repair. Trends Neurosci 2008; 31:146–53.PubMedCrossRefGoogle Scholar
  24. 24.
    Andrews PW, Benvenisty N, McKay R, Pera MF, Rossant J, Semb H, et al. The International Stem Cell Initiative: Toward benchmarks for human embryonic stem cell research. Nat Biotechnol 2005; 23:795–7.PubMedCrossRefGoogle Scholar
  25. 25.
    Binder DK, Rau GM. Starr PA. Risk factors for hemorrhage during microelectrode-guided deep brain stimulator implantation for movement disorders. Neurosurgery 2005; 56:722–32.PubMedCrossRefGoogle Scholar
  26. 26.
    Sansur CA, Frysinger RC, Pouratian N, Fu KM, Bittl M, Oskouian RJ, et al. Incidence of symptomatic hemorrhage after stereotactic electrode placement. J Neurosurg. 2007; 107:998–1003.PubMedCrossRefGoogle Scholar
  27. 27.
    Seijo FJ, Alvarez-Vega MA, Gutierrez JC, Fdez-Glez F, Lozano B. Complications in subthalamic nucleus stimulation surgery for treatment of Parkinson’s disease. Review of 272 procedures. Acta Neurochir (Wien). 2007; 149:867–75.CrossRefGoogle Scholar
  28. 28.
    Weaver FM, Follett K, Stern M, Hur K, Harris C, Marks WJ, et al. Bilateral deep brain stimulation vs. best medical therapy for patients with advanced Parkinson’s disease: A randomized controlled trial. JAMA 2009; 301:63–73.PubMedCrossRefGoogle Scholar
  29. 29.
    Committee for Medicinal Products for Medicinal Use (CHMP). Draft, Guidelines on Requirements for First-in-Man Clinical Trials for Potential High-Risk Medicinal Products. London: Committee for Medicinal Products for Medicinal Use; 22 March 2007. Doc. Ref. EMEA/CHMP/28367/2007.Google Scholar
  30. 30.
    Department of Health and Human Services (US). 2002. Guidance for Industry and Reviewers. Estimating the Safe Starting Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers. US DHHS, CBER December 2002. Draft Guidance.Google Scholar
  31. 31.
    Djulbegovic B. Articulating and responding to uncertainties in clinical research. J Med Philos 2007; 32:79–98.PubMedCrossRefGoogle Scholar
  32. 32.
    Anderson J. Kimmelman J. Extending clinical equipoise to phase 1 trials involving patients: Unresolved problems. Kennedy Inst Ethics J 2010; 20:75–98.PubMedCrossRefGoogle Scholar
  33. 33.
    McLaughlin D, Kimmelman J. (Abstract 537) Human studies of basic investigations: Patterns of citation for gene therapy phase 1 clinical trials in malignant glioma. Mol Ther 2007; 15(S1):S207.Google Scholar
  34. 34.
    Albelda SM, Sterman DH. TNFerade to the rescue? Guidelines for evaluating phase I cancer gene transfer trials. J Clin Oncol 2004; 22:577–9.PubMedCrossRefGoogle Scholar
  35. 35.
    DeYoung MB, Dichek DA. Gene therapy for restenosis: Are we ready? Circ Res 1998; 82:306–13.PubMedCrossRefGoogle Scholar
  36. 36.
    London AJ. Reasonable risks in clinical research: A critique and a proposal for the Integrative Approach. Stat Med 2006; 25:2869–85.PubMedCrossRefGoogle Scholar
  37. 37.
    Philip M, Benatar M, Fisher M, Savitz SI. Methodological quality of animal studies of neuroprotective agents currently in phase II/III acute ischemic stroke trials. Stroke 2009; 40:577–81.PubMedCrossRefGoogle Scholar
  38. 38.
    Perel P, Roberts I, Sena E, Wheble P, Briscoe C, Sandercock P, et al. Comparison of treatment effects between animal experiments and clinical trials: Systematic review. BMJ 2007; 334:197.PubMedCrossRefGoogle Scholar
  39. 39.
    MacLeod MR, O’Collins T, Howells DW, Donnan GA. Pooling of animal experimental data reveals influence of study design and publication bias. Stroke 2004; 35:1203–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Bebarta V, Luyten D, Heard K. Emergency medicine animal research: Does use of randomization and blinding affect the results? Acad Emerg Med 2003; 10:684–7.PubMedGoogle Scholar
  41. 41.
    Benatar M. Lost in translation: Treatment trials in the SOD1 mouse and in human ALS. Neurobiol Dis 2007; 26:1–13.PubMedCrossRefGoogle Scholar
  42. 42.
    Macleod MR, O’Collins T, Horky LL, Howells DW, Donnan GA. 2005. Systematic review and meta-analysis of the efficacy of FK506 in experimental stroke. J Cereb Blood Flow Metab 2005; 25:713–21.PubMedCrossRefGoogle Scholar
  43. 43.
    Gladstone DJ, Black SE, Hakim AM. Toward wisdom from failure: Lessons from neuroprotective stroke trials and new therapeutic directions. Stroke 2002; 33:2123–36.PubMedCrossRefGoogle Scholar
  44. 44.
    Lowenstein PR, Castro GM. Uncertainty in the translation of preclinical experiments to clinical trials. Why do most phase III clinical trials fail? Curr Gene Ther 2009; 9:368–74.PubMedCrossRefGoogle Scholar
  45. 45.
    King, N. Therapeutic Overestimation in Early-Phase Clinical Research. Seminar in the Clinical Trials Research Group Seminar Series, McGill University, Friday, April 28, 2008.Google Scholar
  46. 46.
    Horng S, Grady C. Misunderstanding in clinical research: Distinguishing therapeutic misconception, therapeutic misconception and therapeutic optimism. IRB 2003; 25:11–6.PubMedCrossRefGoogle Scholar
  47. 47.
    Kimmelman J. Stable ethics: Enrolling non-treatment-refractory volunteers in novel gene transfer trials. Mol Ther 2007 Nov; 15:1904–6.PubMedCrossRefGoogle Scholar
  48. 48.
    World Medical Association. Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects. Geneva: World Medical Association, 2000.Google Scholar
  49. 49.
    Council for International Organizations of Medical Sciences (CIOMS). International Ethical Guidelines for Biomedical Research Involving Human Subjects. Geneva: CIOMS, 2002.Google Scholar
  50. 50.
    Nuffield Council on Bioethics. The Ethics of Clinical Research in Developing Countries:A discussion paper. London: Nuffield Council on Bioethics, 1999.Google Scholar
  51. 51.
    Nuffield Council on Bioethics. The Ethics of Research Related to Healthcare in Developing Countries: A follow-up discussion paper. London: Nuffield Council on Bioethics, 2005.Google Scholar
  52. 52.
    European Group on Ethics and Science of New Technologies to the European Commission. Opinion on the Ethical Aspects of Clinical Research in Developing Countries: Opinion #17. Luxembourg: Office for Official Publications of the European Communities, 2003.Google Scholar
  53. 53.
    Department of Health. Guidelines for Good Practice in the Conduct of Clinical Trials in Human Participants in South Africa. Johannesburg: Department of Health, 2000.Google Scholar
  54. 54.
    Indian Council of Medical Research. Ethical Guidelines for Biomedical Research on Human Participants. New Delhi: Royal Offset Printers, 2006.Google Scholar
  55. 55.
    Acharya GP, Gywali K, Adhikari RK, Thaler JL. Eds. 2001. National Ethical Guidelines for Health Research in Nepal. Available at: [last accessed January 18, 2010)].
  56. 56.
    London AJ, Kimmelman J. Justice in translation: From the bench to bedside in the developing world. Lancet 2008; 372:82–5.PubMedCrossRefGoogle Scholar
  57. 57.
    Aiuti A, Slavin S, Aker M, Ficara F, Deola S, Mortellaro A, et al. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science 2002; 296:2410–3.PubMedCrossRefGoogle Scholar
  58. 58.
    Kimmelman J. Clinical trials and SCID row: The ethics of phase 1 trials in the developing world. Dev World Bioeth 2007; 7:128–35.PubMedGoogle Scholar
  59. 59.
    Perin EC, Dohmann HF, Borojevic R, Silva SA, Sousa AL, Mesquita CT, et al. Transendocardial, autologous bone-marrow cell transplantation for severe, chronic, ischemic heart failure. Circulation 2003; 107:2294–302.PubMedCrossRefGoogle Scholar
  60. 60.
    Patel AN, Geffner L. Vina RF, Saslavsky J, Urschel HC Jr, Kormos R, et al. 2005. Surgical treatment for congestive heart failure with autologous adult stem cell transplantation: A prospective randomized study. J Thorac Cardiovasc Surg 2005; 130:1631–8.PubMedCrossRefGoogle Scholar
  61. 61.
    Lo B, Zettler P, Cedars MI, Gates E, Kriegstein AR, Oberman M, et al. A new era in the ethics of human embryonic stem cell research. Stem Cells 2005; 23:1454–9.PubMedCrossRefGoogle Scholar
  62. 62.
    Cheng JD, Hitt J, Koczwara B, Schulman KA, Burnett CB, Gaskin DJ, et al. Impact of quality of life on patient expectations regarding phase I clinical trials. J Clin Oncol 2000; 18:421–8.PubMedGoogle Scholar
  63. 63.
    Daugherty C, Ratain MJ, Grochowski E, Stocking C, Kodish E, Mick R, et al. Perceptions of cancer patients and their physicians involved in phase I trials. J Clin Oncol 1995 May; 13:1062–72.PubMedGoogle Scholar
  64. 64.
    Weinfurt K. Value of high-cost cancer care: A behavioral science perspective. J Clin Oncol 2007; 25:223–7.PubMedCrossRefGoogle Scholar
  65. 65.
    Camerer C, Weber M. Recent developments in modeling preferences: Uncertainty and ambiguity. J Risk Uncertain 1992; 5:325–70.CrossRefGoogle Scholar
  66. 66.
    National Institutes of Health. NIH Guidance on Informed Consent for Gene Transfer Research. Department of Health and Human Services, 2003. Accessed at on December 14, 2009.
  67. 67.
    Zarzeczny A, Scott C, Hyun I, Bennett J, Chandler J, Charge S, et al. iPS cells: Mapping the policy issues. Cell 2009; 139:1032–7.PubMedCrossRefGoogle Scholar
  68. 68.
    Food and Drug Administration. Eligibility Determinations for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products, 2005. 21 CFR Parts 210, 211, 820, and 1271.Google Scholar
  69. 69.
    National Academy of Science. Guidelines for Human Embryonic Stem Cell Research. Washington: National Academy Press, 2005.Google Scholar
  70. 70.
    Institute of Medicine. Responsible Research: A Systems Approach to Protecting Research Participants. Washington: National Academic Press, 2003.Google Scholar
  71. 71.
    King N. RAC oversight of gene transfer research: A model worth extending? J Law Med Ethics 2002; 30:381–9.PubMedCrossRefGoogle Scholar
  72. 72.
    Levine C, Faden R, Grady C, Hammerschmidt D, Eckenwiler L, Sugarman J. Consortium to examine clinical research ethics. Ann Intern Med 2004; 140:220–3.PubMedCrossRefGoogle Scholar
  73. 73.
    Kimmelman J, Baylis F, Glass KC. Stem cell trials: Lessons from gene transfer research. Hastings Cent Rep 2006; 36:23–6.PubMedCrossRefGoogle Scholar
  74. 74.
    Report and Recommendations of the Panel to Assess the NIH Investment in Research on Gene Therapy (1995) – A report commissioned by the Director, NIH to advise the NIH on research on gene therapy. Available at: [last accessed January 20, 2010)].

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • James A. Anderson
    • 1
  • Jonathan Kimmelman
    • 2
  1. 1.Biomedical Ethics UnitMcGill UniversityMontrealCanada
  2. 2.Biomedical Ethics/Social Studies of Medicine/Dept Human GeneticsMcGill UniversityMontrealCanada

Personalised recommendations