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Ethical Issues in Phase I Cancer Clinical Trials

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Abstract

Phase I clinical trials in oncology are designed to study the toxicity of novel drugs and regimens in a small cohort of subjects and to establish a dose that can be used in future studies. Due to the toxicity of many antineoplastic therapies, these trials are typically conducted in subjects with advanced cancer and limited therapeutic options. Patients primarily enrol in phase I cancer trials with high expectations of personal medical benefit; however, the risks and benefits of these regimens are unknown and the benefit from enrolment in phase I cancer trials to date has been modest.

The use of a vulnerable population with high expectations of benefit in a scientific experiment creates challenges for the protection of human research subjects. To ethically use one human being for the benefit of others in a phase I oncology trial requires that the research subject never be viewed merely as a means to an end, but that their interests as a person are always respected and safeguarded. This process begins with trial conception and continues even after completion of the trial.

In trial design, particular attention should be given to the nature of the experimental agent or regimen and the most appropriate dose selection and escalation strategy and study endpoint. Older paradigms of inter-patient dose escalation and the establishment of maximally tolerated dose may not be appropriate for all studies. Once a well designed study has been established, the primary challenge is to ensure the voluntary informed consent of research participants. This process involves an explanation of the rationale for the study and details of what study participation actually involves in terms of schedules, drug administration, tests and procedures, and predicted toxicities. It also involves an explanation of the nature of phase I clinical trials with a focus on the nature of uncertainty in terms of risks and benefits, differences between trial care and prior care outside a trial, and the disclosure of any potential conflicts of interest and how these will be mediated.

Phase I oncology trials are critically important in the advance of the care of future cancer patients, but such advances must be achieved on a foundation of respect for today’s patients. Trial design and enrolment must be conducted in a way that lets those who choose to participate do so in a way that also maximises their chance of medical benefit, minimises their risk of harm, and maintains the principle of respect for persons at all times.

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References

  1. Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer J Clin 2005; 55: 74–108

    Article  PubMed  Google Scholar 

  2. Roberts Jr TG, Goulart BH, Squitieri L, et al. Trends in the risks and benefits to patients with cancer participating in phase 1 clinical trials. JAMA 2004; 292: 2130–40

    Article  CAS  PubMed  Google Scholar 

  3. Daugherty CK. Ethical issues in the development of new agents. Invest New Drugs 1999; 17: 145–53

    Article  CAS  PubMed  Google Scholar 

  4. Annas G, Grodin M. The Nazi doctors and the Nuremberg code: human rights in human experimentation. New York: Oxford University Press, 1992

    Google Scholar 

  5. The Nuremberg Code. Reprinted in trials of war criminals before the Nuremberg military tribunals under control council law no. 10. Washington, DC: US Government Printing Office, 1949: 181–2

    Google Scholar 

  6. World Medical Association. Declaration of Helsinki (1964). BMJ 1996; 313: 1448–9

    Google Scholar 

  7. Brandt AM. Racism and research: the case of the Tuskegee Syphilis Study. Hastings Cent Rep 1978; 8: 21–9

    CAS  PubMed  Google Scholar 

  8. Beecher HK. Ethics and clinical research. N Engl J Med 1966; 274: 1354–60

    Article  CAS  PubMed  Google Scholar 

  9. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont report. Appendix, chapter 9. Vol 1. Washington, DC: US Government Printing Office, 1978

    Google Scholar 

  10. Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA 2000; 283: 2701–11

    Article  CAS  PubMed  Google Scholar 

  11. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. Guideline for good clinical practice [online]. Available from URL: http://www.emea.eu.int/pdfs/human/ich/013595en.pdf [Accessed 2006 Jul 14]

  12. Miller M. Phase I cancer trials: a collusion of misunderstanding. Hastings Cent Rep 2000; 30: 34–43

    CAS  PubMed  Google Scholar 

  13. Smith TL, Lee JJ, Kantarjian HM, et al. Design and results of phase I cancer clinical trials: three-year experience at M.D. Anderson Cancer Center. J Clin Oncol 1996; 14: 287–95

    CAS  PubMed  Google Scholar 

  14. Stadler WM, Ratain MJ. Development of target-based antineoplastic agents. Invest New Drugs 2000; 18: 7–16

    Article  CAS  PubMed  Google Scholar 

  15. Dent SF, Eisenhauer EA. Phase I trial design: are new methodologies being put into practice? Ann Oncol 1996; 7: 561–6

    Article  CAS  PubMed  Google Scholar 

  16. Parulekar WR, Eisenhauer EA. Phase I trial design for solid tumor studies of targeted, non-cytotoxic agents. theory and practice. J Natl Cancer Inst 2004; 96: 990–7

    Article  CAS  PubMed  Google Scholar 

  17. Jayson GC, Zweit J, Jackson A, et al. Molecular imaging and biological evaluation of HuMV833 anti-VEGF antibody: implications for trial design of antiangiogenic antibodies. J Natl Cancer Inst 2002; 94: 1484–93

    Article  CAS  PubMed  Google Scholar 

  18. Kodish E, Stocking C, Ratain MJ, et al. Ethical issues in phase I oncology research: a comparison of investigators and institutional review board chairpersons. J Clin Oncol 1992; 10: 1810–6

    CAS  PubMed  Google Scholar 

  19. Joffe S, Weeks JC. Views of American oncologists about the purposes of clinical trials. J Natl Cancer Inst 2002; 94: 1847–53

    Article  PubMed  Google Scholar 

  20. Appelbaum PS, Roth LH, Lidz C. The therapeutic misconception: informed consent in psychiatric research. Int J Law Psychiatry 1982; 5: 319–29

    Article  CAS  PubMed  Google Scholar 

  21. Henderson GE, Easter MM, Zimmer C, et al. Therapeutic misconception in early phase gene transfer trials. Soc Sci Med 2006; 62: 239–53

    Article  PubMed  Google Scholar 

  22. Miller FG, Rosenstein DL. The therapeutic orientation to clinical trials. N Engl J Med 2003; 348: 1383–6

    Article  PubMed  Google Scholar 

  23. Joffe S, Cook EF, Cleary PD, et al. Quality of informed consent: a new measure of understanding among research subjects. J Natl Cancer Inst 2001; 93: 139–47

    Article  CAS  PubMed  Google Scholar 

  24. Henderson G. Measuring research understanding: establishing a valid and practical definition of patient-subjects. Therapeutic Misconception Conference; 2005 Sep; Columbia (SC).

    Google Scholar 

  25. Gordon EJ, Daugherty CK. Referral and decision making among advanced cancer patients participating in phase I trials at a single institution. J Clin Ethics 2001; 12: 31–8

    CAS  PubMed  Google Scholar 

  26. Nurgat ZA, Craig W, Campbell NC, et al. Patient motivations surrounding participation in phase I and phase II clinical trials of cancer chemotherapy. Br J Cancer 2005; 92: 1001–5

    Article  CAS  PubMed  Google Scholar 

  27. Weinfurt KP, Castel LD, Li Y, et al. The correlation between patient characteristics and expectations of benefit from phase I clinical trials. Cancer 2003; 98: 166–75

    Article  PubMed  Google Scholar 

  28. Meropol NJ, Weinfurt KP, Burnett CB, et al. Perceptions of patients and physicians regarding phase I cancer clinical trials: implications for physician-patient communication. J Clin Oncol 2003; 21: 2589–96

    Article  PubMed  Google Scholar 

  29. Weinfurt KP, Sulmasy DP, Schulman KA, et al. Patient expectations of benefit from phase I clinical trials: linguistic considerations in diagnosing a therapeutic misconception. Theor Med Bioeth 2003; 24: 329–44

    Article  CAS  PubMed  Google Scholar 

  30. Horstmann E, McCabe MS, Grochow L, et al. Risks and benefits of phase 1 oncology trials, 1991 through 2002. N Engl J Med 2005; 352: 895–904

    Article  CAS  PubMed  Google Scholar 

  31. Agrawal M, Emanuel EJ. Ethics of phase 1 oncology studies: reexamining the arguments and data. JAMA 2003; 290: 1075–82

    Article  PubMed  Google Scholar 

  32. Horng S, Emanuel EJ, Wilfond B, et al. Descriptions of benefits and risks in consent forms for phase 1 oncology trials. N Engl J Med 2002; 347: 2134–40

    Article  PubMed  Google Scholar 

  33. Edwards SJ, Lilford RJ, Thornton J, et al. Informed consent for clinical trials: in search of the “best” method. Soc Sci Med 1998; 47: 1825–40

    Article  CAS  PubMed  Google Scholar 

  34. Coyne CA, Xu R, Raich P, et al. Randomized, controlled trial of an easy-to-read informed consent statement for clinical trial participation: a study of the Eastern Cooperative Oncology Group. J Clin Oncol 2003; 21: 836–42

    Article  PubMed  Google Scholar 

  35. Joffe S, Cook EF, Cleary PD, et al. Quality of informed consent in cancer clinical trials: a cross-sectional survey. Lancet 2001; 358: 1772–7

    Article  CAS  PubMed  Google Scholar 

  36. Sollitto S, Hoffman S, Mehlman M, et al. Intrinsic conflicts of interest in clinical research: a need for disclosure. Kennedy Inst Ethics J 2003; 13: 83–91

    Article  PubMed  Google Scholar 

  37. Morin K, Rakatansky H, Riddick Jr FA, et al. Managing conflicts of interest in the conduct of clinical trials. JAMA 2002; 287: 78–84

    Article  PubMed  Google Scholar 

  38. Kim SY, Millard RW, Nisbet P, et al. Potential research participants’ views regarding researcher and institutional financial conflicts of interest. J Med Ethics 2004; 30: 73–9

    Article  CAS  PubMed  Google Scholar 

  39. Camacho LH, Bacik J, Cheung A, et al. Presentation and subsequent publication rates of phase I oncology clinical trials. Cancer 2005; 104: 1497–504

    Article  PubMed  Google Scholar 

  40. Krzyzanowska MK, Pintilie M, Tannock IF. Factors associated with failure to publish large randomized trials presented at an oncology meeting. JAMA 2003; 290: 495–501

    Article  PubMed  Google Scholar 

  41. Partridge AH, Wong JS, Knudsen K, et al. Offering participants results of a clinical trial: sharing results of a negative study. Lancet 2005; 365: 963–4

    Article  PubMed  Google Scholar 

  42. (PhRMA) PRaMoA. Pharmaceutical industry profile 2003. Washington, DC: PhRMA, 2003: 11

    Google Scholar 

  43. Djulbegovic B, Lacevic M, Cantor A, et al. The uncertainty principle and industry- sponsored research. Lancet 2000; 356: 635–8

    Article  CAS  PubMed  Google Scholar 

  44. Peppercorn JM, Blood E, Winer EP, et al. Pharmaceutical involvement in breast cancer clinical trials proceedings of the American Society Of Clinical Oncology [abstract 6057]. J Clin Oncol 2005; 23 (Jun Suppl. 1). 2005 ASCO Annual Meeting Proceedings; 2005 May 12–16; Orlando (FL).

  45. American Society of Clinical Oncology. Revisions of and clarifications to the ASCO conflict of interest policy. J Clin Oncol 2006; 24: 517–8

    Article  Google Scholar 

  46. Couzin J. Drug research: legislators propose a registry to track clinical trials from start to finish. Science 2004; 305: 1695

    Article  CAS  PubMed  Google Scholar 

  47. Smith M, Bernstein M, Bleyer WA, et al. Conduct of phase I trials in children with cancer. J Clin Oncol 1998; 16: 966–78

    CAS  PubMed  Google Scholar 

  48. Aleksa K, Koren G. Ethical issues in including pediatric cancer patients in drug development trials. Paediatr Drugs 2002; 4: 257–65

    PubMed  Google Scholar 

  49. Lee DP, Skolnik JM, Adamson PC. Pediatric phase I trials in oncology: an analysis of study conduct efficiency. J Clin Oncol 2005; 23: 8431–41

    Article  PubMed  Google Scholar 

  50. Kauffman RE. Clinical trials in children: problems and pitfalls. Paediatr Drugs 2000; 2: 411–8

    Article  CAS  PubMed  Google Scholar 

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  1. Division of Hematology and Oncology, University of North Carolina at Chapel Hill, CB# 7305, 3009 Old Clinic, Chapel Hill, NC, 27514, USA

    Jeffrey Peppercorn

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  1. Jeffrey Peppercorn
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Correspondence to Jeffrey Peppercorn.

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Peppercorn, J. Ethical Issues in Phase I Cancer Clinical Trials. Int J Pharm Med 20, 233–242 (2006). https://doi.org/10.2165/00124363-200620040-00003

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