Ethics of Cancer Gene Transfer Clinical Research

  • Jonathan KimmelmanEmail author
Part of the Methods in Molecular Biology™ book series (MIMB, volume 542)


Cancer gene transfer is a relatively novel intervention strategy. In part because of this novelty, trials often present greater uncertainties than those investigating more conventional approaches. In the following review, I examine how this greater uncertainty might affect how clinical studies are designed, when they are initiated, their degree of risk, and whether such risk can be justified in terms of therapeutic benefit. The review also discusses two other ethical issues presented by gene transfer clinical research: fairness in subject selection and communications with the public. I conclude with a series of recommendations directed toward researchers, policymakers, and ethics committee members.


Cancer correlative studies ethics gene transfer informed consent phase 1 risk uncertainty value 



This work was funded by the Canadian Institutes of Health Research.


  1. 1.
    The National Commission for the Protection of Human Subjects of Biomedical and Behavioural Research (1979) The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. (Department of Health, Education, and Welfare, ed).Google Scholar
  2. 2.
    Medical Research Council of Canada (2003) Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans.Google Scholar
  3. 3.
    World Medical Association (1964) Declaration of Helsinki.Google Scholar
  4. 4.
    Rainsbury, J. M. (2000) Biotechnology on the RAC--FDA/NIH regulation of human gene therapy. Food Drug Law J. 55, 575–600.PubMedGoogle Scholar
  5. 5.
    King, N. M. (2002) RAC oversight of gene transfer research: a model worth extending? J. Law. Med. Ethics 30, 381–389.PubMedCrossRefGoogle Scholar
  6. 6.
    Cornetta, K., and Smith, F.O. (2002) Regulatory issues for clinical gene therapy trials. Hum. Gene Ther. 13, 1143–1149.PubMedCrossRefGoogle Scholar
  7. 7.
    Holzen, U. W., and Swisher, S.G. (2007) In Cancer Drug Discovery and Development: Gene Therapy for Cancer (Hunt, K.K., et al., eds), Humana Press, Totowa, NJ.Google Scholar
  8. 8.
    Wallace, J. (2000) Humane endpoints and cancer research. ILAR J. 41, 87–93.PubMedGoogle Scholar
  9. 9.
    Klein, H. J., and Bayne, K. A. (2007) Establishing a culture of care, conscience, and responsibility: addressing the improvement of scientific discovery and animal welfare through science-based performance standards. ILAR J. 48, 3–11.PubMedGoogle Scholar
  10. 10.
    United Kingdom Co-ordinating Committee on Cancer Research (UKCCCR) (1998) Guidelines for the Welfare of Animals in Experimental Neoplasia (Second Edition). Br. J. Cancer 77, 1–10.Google Scholar
  11. 11.
    DeGrazia, D. (1996) Taking Animanls Seriously: Mental Life and Moral Status. Cambridge University Press, New York.Google Scholar
  12. 12.
    Daugherty, C. K. (1999) Ethical issues in the development of new agents. Invest. New Drugs 17, 145–153.PubMedCrossRefGoogle Scholar
  13. 13.
    Daugherty, C. K., et al. (2000) Quantitative analysis of ethical issues in phase I trials: a survey interview of 144 advanced cancer patients. IRB. 22, 6–14.PubMedCrossRefGoogle Scholar
  14. 14.
    Jayson, G., and Harris, J. (2006) How participants in cancer trials are chosen: ethics and conflicting interests. Nat. Rev. Cancer 6, 330–336.PubMedCrossRefGoogle Scholar
  15. 15.
    Daugherty, C. K. (2000) Informed consent, the cancer patient, and phase I clinical trials. Cancer Treat. Res. 102, 77–89.PubMedGoogle Scholar
  16. 16.
    Grunwald, H. W. (2007) Ethical and Design Issues of Phase I Clinical Trials in Cancer Patients. Cancer Invest. 25, 124–126.PubMedCrossRefGoogle Scholar
  17. 17.
    Djulbegovic, B. (2007) Articulating and responding to uncertainties in clinical research. J. Med. Philos. 32, 79–98.PubMedCrossRefGoogle Scholar
  18. 18.
    Kimmelman, J. (2005) Recent developments in gene transfer: risk and ethics. BMJ 330, 79–82.PubMedCrossRefGoogle Scholar
  19. 19.
    Morral, N., et al. (2002) Lethal toxicity, severe endothelial injury, and a threshold effect with high doses of an adenoviral vector in baboons. Hum. Gene Ther. 13, 143–154.PubMedCrossRefGoogle Scholar
  20. 20.
    Halpern, S. D., et al. (2002) The continuing unethical conduct of underpowered clinical trials. JAMA 288, 358–362.PubMedCrossRefGoogle Scholar
  21. 21.
    U.S. Food and Drug Administration (2007) Drugs for Human Use: Investigational New Drug Application 21CFR312.21(a). (Department of Health and Human Services, ed).Google Scholar
  22. 22.
    DiMasi, J.A., and Grabowski, H.G. (2007) Economics of new oncology drug development. J. Clin. Oncol. 25, 209–216.PubMedCrossRefGoogle Scholar
  23. 23.
    Search GEMCRIS using Medical condition “cancer”; December 5, 2007. Note that GEMCRIS is not a complete listing of all GT cancer studies (protocols of studies pursued outside of institutions receiving NIH funds are not always submitted to OBA); note also that not all studies registered with OBA are actually initiated or completed.Google Scholar
  24. 24.
    Wiley. Searched December 5, 2007. For purposes of calculation, phase 1–2 studies were counted as phase 1; phase 2–3 studies were counted as phase 2.Google Scholar
  25. 25.
    Orkin, S.H., and Motulsky, A.G. (1995) Report and Recommendations of the Panel to Asses the NIH Investment in Research on Gene Therapy. (National Institutes of Health - Office of Biotechnology Activities, ed).Google Scholar
  26. 26.
    Albelda, S.M., and Sterman, D.H. (2004) TNFerade to the rescue? Guidelines for evaluating phase I cancer gene transfer trials. J. Clin. Oncol. 22, 577–579.PubMedCrossRefGoogle Scholar
  27. 27.
    Freedman, B. (1987) Equipoise and the ethics of clinical research. N. Engl. J. Med. 317, 141–145.PubMedCrossRefGoogle Scholar
  28. 28.
    London, A.J. (2007) Clinical Equipoise: Foundational Requirement or Fundamental Error? In The Oxford Handbook of Bioethics (Steinbock, B., ed), Oxford University Press, New York.Google Scholar
  29. 29.
    Schou, K. C., and Hewison, J. (1999) Experiencing Cancer: Quality of Life in Treatment. Open University Press, Buckingham.Google Scholar
  30. 30.
    Dirnagl, U. (2006) Bench to bedside: the quest for quality in experimental stroke research. J. Cereb. Blood Flow Metab. 26, 1465–1478.PubMedCrossRefGoogle Scholar
  31. 31.
    Lee, D. S., et al. (2003) Meta-analysis of the effects of endothelin receptor blockade on survival in experimental heart failure. J. Card. Fail. 9, 368–374.PubMedCrossRefGoogle Scholar
  32. 32.
    Bebarta, V., et al. (2003) Emergency medicine animal research: does use of randomization and blinding affect the results? Acad. Emerg. Med. 10, 684–687.PubMedGoogle Scholar
  33. 33.
    Australian Government (2004) Australian Code of Practice for the Care and Use of Animals for Scientific Purposes, 7th Edition. (7 edn) (National Health and Medical Research Council, ed).Google Scholar
  34. 34.
    Organisation for Economic Co-operation and Development (2000) Guidance Document on the Recognition, Assessment and Use of Clinical Signs as Humane Endpoints. Series on Testing and Assessment Volume, 20.Google Scholar
  35. 35.
    UK Co-ordinating Committee on Cancer Research (1997) UKCCCR Guidelines for the Welfare of Animals in Experimental Neoplasia (2nd Edition).Google Scholar
  36. 36.
    Kamb, A. (2005) What's wrong with our cancer models? Nat. Rev. Drug Discov. 4, 161–165.PubMedCrossRefGoogle Scholar
  37. 37.
    Sharpless, N. E., and DePinho, R. A. (2006) The mighty mouse: genetically engineered mouse models in cancer drug development. Nat. Rev. Drug Discov. 5, 741–754.PubMedCrossRefGoogle Scholar
  38. 38.
    Hansen, K., and Khanna, C. (2004) Spontaneous and genetically engineered animal models; use in preclinical cancer drug development. Eur. J. Cancer 40, 858–880.PubMedCrossRefGoogle Scholar
  39. 39.
    Knapp, D. W., and Waters, D. J. (1997) Naturally occurring cancer in pet dogs: important models for developing improved cancer therapy for humans. Mol. Med. Today 3, 8–11.PubMedCrossRefGoogle Scholar
  40. 40.
    Khanna, C., et al. (2006) The dog as a cancer model. Nat. Biotech. 24, 1065–1066.CrossRefGoogle Scholar
  41. 41.
    Pet Food Institute (2006) Pet Dog & Cat Population. Washington, DC.Google Scholar
  42. 42.
    Kimmelman, J., and Nalbantoglu, J. (2007) Faithful companions: a proposal for neurooncology trials in pet dogs. Cancer Res. 67, 4541–4544.PubMedCrossRefGoogle Scholar
  43. 43.
    Tjin Tham Sjin, R. M., et al. (2006) Endostatin therapy reveals a U-shaped curve for antitumor activity. Cancer Gene Ther. 13, 619–627.PubMedCrossRefGoogle Scholar
  44. 44.
    Kamstock, D., et al. (2006) Liposome-DNA complexes infused intravenously inhibit tumor angiogenesis and elicit antitumor activity in dogs with soft tissue sarcoma. Cancer Gene Ther. 13, 306–317.PubMedCrossRefGoogle Scholar
  45. 45.
    Dow, S., et al. (2005) Phase I study of liposome-DNA complexes encoding the interleukin-2 gene in dogs with osteosarcoma lung metastases. Hum. Gene Ther. 16, 937–946.PubMedCrossRefGoogle Scholar
  46. 46.
    National Cancer Institute Center for Cancer Research (2006) Comparative Oncology Program.
  47. 47.
    Zabner, J., et al. (1993) Adenovirus-mediated gene transfer transiently corrects the chloride transport defect in nasal epithelia of patients with cystic fibrosis. Cell 75, 207–216.PubMedCrossRefGoogle Scholar
  48. 48.
    Zabner, J., et al. (1996) Repeat administration of an adenovirus vector encoding cystic fibrosis transmembrane conductance regulator to the nasal epithelium of patients with cystic fibrosis. J. Clin. Invest. 97, 1504–1511.PubMedCrossRefGoogle Scholar
  49. 49.
    Mendell, J. R., et al. (1995) Myoblast transfer in the treatment of Duchenne's muscular dystrophy. N. Engl. J. Med. 333, 832–838.PubMedCrossRefGoogle Scholar
  50. 50.
    Kimmelman, J. (2007) Ethics at phase 0: clarifying the issues. J. Law. Med. Ethics 35, 727–733.PubMedCrossRefGoogle Scholar
  51. 51.
    Agulnik, M., et al. (2006) Impact and perceptions of mandatory tumor biopsies for correlative studies in clinical trials of novel anticancer agents. J. Clin. Oncol. 24, 4801–4807.PubMedCrossRefGoogle Scholar
  52. 52.
    Harrington, K. J., et al. (2005) Gene therapy for head and neck cancer. Cancer Metastasis Rev. 24, 147–164.PubMedCrossRefGoogle Scholar
  53. 53.
    Penuelas, I., et al. (2005) Gene therapy imaging in patients for oncological applications. Eur. J. Nucl. Med. Mol. Imaging 32(Suppl 2), S384–403.PubMedCrossRefGoogle Scholar
  54. 54.
    Iyer, M., et al. (2005) Applications of molecular imaging in cancer gene therapy. Curr. Gene Ther. 5, 607–618.PubMedCrossRefGoogle Scholar
  55. 55.
    Kristian Raty, J., et al. (2007) Non-invasive Imaging in Gene Therapy. Mol. Ther. 15, 1579–1586.CrossRefGoogle Scholar
  56. 56.
    Recombinant DNA Advisory Committee (RAC) (1998) Minutes of Meeting September 24–25. (Department of Health and Human Services, ed), 1–50.Google Scholar
  57. 57.
    Prados, M. D., et al. (2003) Treatment of progressive or recurrent glioblastoma multiforme in adults with herpes simplex virus thymidine kinase gene vector-producer cells followed by intravenous ganciclovir administration: a phase I/II multi-institutional trial. J. Neurooncol. 65, 269–278.PubMedCrossRefGoogle Scholar
  58. 58.
    Of course, there are likely to be exceptions. Cancer vaccines studies, for example, will have a different risk profile than those using oncolytic vectors.Google Scholar
  59. 59.
    US Food and Drug Administration, and Center for Drug Evaluation and Research (2005) Guidance for Industry on Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. (Department of Health and Human Services, ed).Google Scholar
  60. 60.
    Liu, T. -C., and Kirn, D. H. (2007) Problems, Side Effects, and Disappointments in Clinical Cancer Gene Therapy. In Gene Therapy for Cancer (Cancer Drug Discovery and Development) (1st edn) (Hunt, K.K., et al., eds), 351–386, Humana Press.Google Scholar
  61. 61.
    Kimmelman, J. (2005) Medical research, risk, and bystanders. IRB. 27, 1–6.PubMedCrossRefGoogle Scholar
  62. 62.
    Liu, S.C., et al. (2002) Anticancer efficacy of systemically delivered anaerobic bacteria as gene therapy vectors targeting tumor hypoxia/necrosis. Gene Ther. 9, 291–296.PubMedCrossRefGoogle Scholar
  63. 63.
    Sasaki, T., et al. (2006) Genetically engineered Bifidobacterium longum for tumor-targeting enzyme-prodrug therapy of autochthonous mammary tumors in rats. Cancer Sci. 97, 649–657.PubMedCrossRefGoogle Scholar
  64. 64.
    Lichtenstein, D. L., and Wold, W. S. (2004) Experimental infections of humans with wild-type adenoviruses and with replication-competent adenovirus vectors: replication, safety, and transmission. Cancer Gene Ther. 11, 819–829.PubMedCrossRefGoogle Scholar
  65. 65.
    Kimmelman, J. (2007) Missing the forest: further thoughts on the ethics of bystander risk in medical research. Camb. Q. Healthcare Ethics 16, 483–490.CrossRefGoogle Scholar
  66. 66.
    Joffe, S., and Miller, F.G. (2006) Rethinking risk-benefit assessment for phase I cancer trials. J. Clin. Oncol. 24, 2987–2990.PubMedCrossRefGoogle Scholar
  67. 67.
    Agrawal, M., and Emanuel, E. J. (2003) Ethics of phase 1 oncology studies: reexamining the arguments and data. JAMA 290, 1075–1082.PubMedCrossRefGoogle Scholar
  68. 68.
    Markman, M. (2006) "Therapeutic intent" in phase 1 oncology trials: a justifiable objective. Arch. Intern. Med. 166, 1446–1448.PubMedCrossRefGoogle Scholar
  69. 69.
    Lidz, C. W., and Appelbaum, P. S. (2002) The therapeutic misconception: problems and solutions. Med. Care 40, V55–63.PubMedCrossRefGoogle Scholar
  70. 70.
    Penman, D. T., et al. (1984) Informed consent for investigational chemotherapy: patients' and physicians' perceptions. J. Clin. Oncol. 2, 849–855.PubMedGoogle Scholar
  71. 71.
    Lipsett, M. B. (1982) On the nature and ethics of phase I clinical trials of cancer chemotherapies. JAMA 248, 941–942.PubMedCrossRefGoogle Scholar
  72. 72.
    Sixty-four percent expect some sort of benefit. Weinfurt, K. P., et al. (2003) The correlation between patient characteristics and expectations of benefit from Phase I clinical trials. Cancer 98, 166–75.Google Scholar
  73. 73.
    Horng, S., and Grady, C. (2003) Misunderstanding in clinical research: distinguishing therapeutic misconception, therapeutic misestimation, and therapeutic optimism. IRB. 25, 11–16.PubMedCrossRefGoogle Scholar
  74. 74.
    Cheng, J. D., et al. (2000) Impact of quality of life on patient expectations regarding phase I clinical trials. J. Clin. Oncol. 18, 421–428.PubMedGoogle Scholar
  75. 75.
    Kimmelman, J. (2007) The therapeutic misconception at 25: treatment, research, and confusion. Hastings Cent. Rep. 37, 36–42.PubMedCrossRefGoogle Scholar
  76. 76.
    Koyfman, S. A., et al. (2007) Risks and benefits associated with novel phase 1 oncology trial designs. Cancer 110, 1115–1124.PubMedCrossRefGoogle Scholar
  77. 77.
    The figure of 1% is controversial. Schneiderman L. J., Jecker N. S., and Jonsen A. R. (1990) Medical Futility: Its Meaning and Ethical Implications. Ann. Intern. Med. 112: 949–954.PubMedGoogle Scholar
  78. 78.
    Schneiderman, L. J., and Jecker, N. S. (1995) Wrong Medicine: Doctors, Patients, and Futile Treatment. John Hopkins University Press, Baltimore, MD.Google Scholar
  79. 79.
    Atkins, M. B., et al. (2004) Update on the role of interleukin 2 and other cytokines in the treatment of patients with stage IV renal carcinoma. Clin. Cancer Res. 10, 6342S–6346S.PubMedCrossRefGoogle Scholar
  80. 80.
    Perhaps one way of summarizing the foregoing discussion is as follows: from an individual patient perspective, discussion of therapeutic benefits is not without a basis. However, from a public policy perspective, it is. Since study protocols and informed consent practices are reviewed at a policy level, it makes more sense for the policy framework to prevail in this context.Google Scholar
  81. 81.
    Kimmelman, J., and Palmour, N. (2005) Therapeutic optimism in the consent forms of phase 1 gene transfer trials: an empirical analysis. J. Med. Ethics 31, 209–214.PubMedCrossRefGoogle Scholar
  82. 82.
    Henderson, G. E., et al. (2004) Uncertain benefit: investigators' views and communications in early phase gene transfer trials. Mol. Ther. 10, 225–231.PubMedCrossRefGoogle Scholar
  83. 83.
    Sankar, P. (2004) Communication and miscommunication in informed consent to research. Med. Anthropol. Q. 18, 429–446.PubMedCrossRefGoogle Scholar
  84. 84.
    Khuri, F. R., et al. (2000) a controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer. Nat. Med. 6, 879–885.PubMedCrossRefGoogle Scholar
  85. 85.
    Sherwin, S. (2005) Belmont Revisited through a Feminist Lens. In Belmont Revisited: Ethical Principles for Research with Human Subjects (Childress, J.F., et-al., eds), 148–164, Georgetown University Press, Washington, DC.Google Scholar
  86. 86.
    Kelly, E., and Russell, S.J. (2007) History of oncolytic viruses: Genesis to genetic engineering. Mol. Ther. 15, 651–659.PubMedCrossRefGoogle Scholar
  87. 87.
    Lerner, B.H. (2004) Sins of omission--cancer research without informed consent. N. Engl. J. Med. 351, 628–630.PubMedCrossRefGoogle Scholar
  88. 88.
    Kahn, J. P., et al. (1998) Changing Claims About Justice in Research: An Introduction and Overview. In Beyond Consent: Seeking Justice in Research (Kahn, J. P., et-al, eds), Oxford University Press, New York.Google Scholar
  89. 89.
    The patient’s husband was chairman of the board of the San Diego Regional Cancer Center, and he prevailed on Iowa’s Senator Tom Harkin to persuade NIH to grant exemption to their usual review procedures.Google Scholar
  90. 90.
    Jenks, S. (1993) RAC approves policy for single-patient use of gene therapy. J. Natl. Cancer Inst. 85, 266–267.PubMedCrossRefGoogle Scholar
  91. 91.
    Lysaught, M. T. (1998) Commentary: reconstruing genetic research as research. J. Law. Med. Ethics 26, 48–54.PubMedCrossRefGoogle Scholar
  92. 92.
    Einhorn, B., et al. (2006) A cancer treatment you can’t get here: China, with lower regulatory hurdles, is racing to a lead in gene therapy. In Bus. Week. March 6, 2006.Google Scholar
  93. 93.
    Jia, H., and Kling, J. (2006) China offers alternative gateway for experimental drugs. Nat. Biotechnol. 24, 117–118.PubMedCrossRefGoogle Scholar
  94. 94.
    Council for International Organizations of Medical Sciences (CIOMS) (2002) International Ethical Guidelines for Biomedical Research Involving Human Subjects. World Health Organization.Google Scholar
  95. 95.
    National Bioethics Advisory Commission (2001) Ethical and Policy Issues in International Research: Clinical Trials in Developing Countries. In Volume I: Report and Recommendations of the National Bioethics Advisory Commission. Google Scholar
  96. 96.
    Nuffield Council on Bioethics (2002) The Ethics of Research Related to Healthcare in Developing Countries.Google Scholar
  97. 97.
    Council for International Organizations of Medical Sciences (CIOMS) (2002) International ethical guidelines for biomedical research involving human subjects. Bull. Med. Ethics 17–23.Google Scholar
  98. 98.
    London, A. J. (2005) Justice and the human development approach to international research. Hastings Cent. Rep. 35, 24–37.PubMedCrossRefGoogle Scholar
  99. 99.
    Which is approximately $2700.Google Scholar
  100. 100.
    Jia, H. (2006) Controversial Chinese gene-therapy drug entering unfamiliar territory. Nat. Rev. Drug Discov. 5, 269–270.PubMedCrossRefGoogle Scholar
  101. 101.
    Staff (2006) China’s War on Cancer. In Red Herring: The Business of Technology April 29, 2006.Google Scholar
  102. 102.
    Advisory Committee on Human Radiation Experiments (1995) Final Report.Google Scholar
  103. 103.
    Kolata, G. (1998) Hope in the Lab: A Special Report; A Cautious Awe Greets Drugs that Eradicate Tumors in Mice. In The New York Times, May 3, 1998; p 1.Google Scholar
  104. 104.
    Bogler, O., and Mikkelsen, T. (2003) Angiogenesis in glioma: molecular mechanisms and roadblocks to translation. Cancer J. 9, 205–213.PubMedCrossRefGoogle Scholar
  105. 105.
    Ryan, D. P., et al. (1999) Reality testing in cancer treatment: the phase I trial of endostatin. Oncologist 4, 501–508.PubMedGoogle Scholar
  106. 106.
    Snyder, L., and Leffler, C. (2005) Ethics manual: fifth edition. Ann. Intern. Med. 142, 560–582.PubMedGoogle Scholar
  107. 107.
    Indian Council of Medical Research (2006) Ethical Guidelines for Biomedical Research on Human Participants.Google Scholar
  108. 108.
    Guidelines on Good Research Practice. The Association of Medical Research Charities.Google Scholar
  109. 109.
    Kimmelman, J. ((expected publication date) 2009) Gene Transfer and the Ethics of First in Human Experiments: Lost in Translation. Cambridge University Press, New York.CrossRefGoogle Scholar

Copyright information

© Humana Press, a part of Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of Social Studies of MedicineBiomedical Ethics Unit/McGill UniversityCanada

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