The physician/investigator's obligation to patients participating in research: The case of placebo controlled trials

Journal of Law, Medicine and Ethics

Volumn 33, Issue 3, 2005, Pages 575-585

  Glass, Kathleen Cranley ^a,b   Waring, Duff ^c  

^a MCGILL UNIVERSITY   (Canada)

^b MONTREAL CHILDREN S HOSPITAL   (Canada)

^c YORK UNIVERSITY   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 27544441694     PISSN: 10731105     EISSN: None     Source Type: Journal    
DOI: 10.1111/j.1748-720X.2005.tb00520.x     Document Type: Article

References (102)

1. F. G. Miller and H. J. Silverman, "The Ethical Relevance of the Standard of Care in the Design of Clinical Trials," American Journal of Respiratory Critical Care Medicine 169, no. 5 (2004): 562-64;
2. F. G. Miller and H. Brody, "The Clinician-investigator: Unavoidable but Manageable Tension," Kennedy Institute Ethics Journal 13, no. 4 (2003): 329-46;
3. F. G. Miller and H. Brody, "What Makes Placebo-controlled Trials Unethical?" American Journal of Bioethics 2, no. 2 (2002): 3-9.
4. F. G. Miller and H. Brody, "A Critique of Clinical Equipoise," Hastings Center Report. 33, no. 3 (2003): 19-28 at 20, 24-25.
5. Id. at 24.
6. Id. at 26-27.
7. R. Temple, "Government Viewpoint of Clinical Trials," Drug Information Journal (1982): 10-17;
8. R. Temple, "Problems in Interpreting Active Control Equivalence Trials," Accountability 4 (1996): 267-75;
9. R. Temple, and S. S. Ellenberg, "Placebo-Controlled Trials and Active-Controlled Trials in the Evaluation of New Treatments," Annals of Internal Medicine 133 (2001): 455-63.
10. K. C. Glass and D. Waring, "Effective Trial Design Need Not Conflict with Good Patient Care," American Journal of Bioethics 2, no. 2 (2002): 25-26;
11. D. Fergusson, K. C. Glass, D. Waring, and S. Shapiro, "Turning a Blind Eye: The Success of Blinding Reported in a Random Sample of Randomized, Placebo-Controlled Trials," British Medical Journal 328, no.7437 (2004): 432-40.
12. Id.; see also F. Benjamin, "Placebo-Controlled Trials and the Logic of Clinical Purpose," IRB: A Review of Human Subjects Research 12 (1990): 1-6;
13. K. J. Rothman and K. B. Michels, "The Continuing Unethical Use of Placebo Controls," N. Engl. J. Med., 331 (1994): 394-98;
14. B. Freedman, K. C. Glass and C. Weijer, "Placebo Orthodoxy in Clinical Research II: Ethical, Legal, and Regulatory Myths," Journal of Law, Medicine & Ethics 24 (1996): 252-59, at 256;
15. K. C. Glass and D. Waring, "Effective Trial Design Need Not Conflict With Good Patient Care," American Journal of Bioethics 2 (2002): 25-26, at 26;
16. F. G. Miller and H. Brody, "What Makes Placebo-Controlled Trials Unethical?" American Journal of Bioethics 2 (2002): 3-9, at 2-5;
17. E. Emanuel and F. G. Miller, "The Ethics of Placebo-Controlled Trials: A Middle Ground," N. Engl J. Med., 345 (2001): 915-19;
18. National Placebo Initiative, Health Canada & Canadian Institute of Health Research, Draft Report of the National Placebo Working Committee (October, 2004).
19. See B. Freedman, K. C. Glass and C. Weijer, supra note 7; K. C. Glass and D. Waring, supra note 6; D. Waring, and K. C. Glass,, "Legal Liability for Harm to Research Subjects in Placebo Controlled Trials" in New Directions in Biomedical Research: Regulation, Conflict of Interest and Liability, T. Lemmens and D. Waring (eds) (Toronto: University of Toronto Press, in press).
20. We are aware of no such judgments. However, a Complaint and Demand for Jury Trial was filed in the Orange County, North Carolina Superior Court by a patient/ plaintiff randomized to the placebo arm of a clinical trial testing a new psoriasis treatment. The plaintiff claimed damages for the development of debilitating psoriatic arthritis resulting from participation in the trial. The trial protocol required discontinuation of his current medication and withholding of the experimental drug. William Hamlet v. Genentech, Inc; Xoma, Ltd.; Western Institutional Review Board, Inc.; Parexel International, LLC; Mark. S. Fradin, M.D.; and Chapel Hill Dermatology, P.A., Superior Court of Justice, Superior Court division 03 CVS 1161, Orange County, North Carolina (July, 2003). Five of the six defendants have settied. Personal communication, Alan Milstein, attorney for the plaintiff, June 8, 2005.
21. M. M. Mello, D. M. Studdart and T. Brennan, "The Rise of Litigation in Human Subjects Research" Annals of Internal Medicine 139 (2003): 40-45.
22. Bok, Universities in the Marketplace (NJ: Princeton, 2003): at 144-50;
23. K. C. Glass and T. M. Lemmens, "Conflict of Interest and Commercialization of Biomedical Research: What is the Role of Research Ethics Review?" in T. Caulfield and B. Williams-Jones, eds., The Commercialization of Genetic Research: Ethical, Legal and Policy Issues (New York: Plenum, 1999): 79-99 at 86-88.
24. D. B. Dobbs, The Law of Torts, vol. 1 (St. Paul, MN: West Publishing Co., 2001): at 269;
25. G. Robertson, "Negligence and Malpractice," in J. Downie, T. Caufield, and C. Flood, eds., Canadian Health Law and Policy, 2d. ed. (Markham, Ontario: Butterworths Canada Ltd., 2002): 91-109, at 91;
26. M. A. Jones, Medical Negligence (London: Sweet and Maxwell, 1991): at 20;
27. D. Giesen, International Medical Malpractice Law: A Comparative Law Study of Civil Liability Arising From Medical Care (Dordrecht: Nijhoff, 1988): at 25, 30-31;
28. J. H. King Jr., The Law of Medical Malpractice in a Nutshell, 2d. ed. (St. Paul, MN: West Publishing Co., 1986): at 9.
29. E. I. Picard and G. B. Robertson, Legal Liability of Doctors and Hospitals in Canada, 3d. ed. (Toronto: Carswell, 1996); Restatement (Second) of Torts § 282 (1965).
30. Miller and Brody, supra note 1, at 3-5; see also Emanuel and Miller, supra note 7, at 915-19.
31. Picard and Robertson, supra note 13, at 1-8.
32. American Medical Association Council on Ethical and Judicial Affairs, Code of Medical Ethics, at 〈www.ama-assn.org/ama/ pub/category/2498. html〉 (last visited June 22, 2005).
33. Id.
34. Id. at Article E-2.07, Clinical Investigation.
35. Declaration of Helsinki (Helsinki: World Medical Association, 52nd General Assembly, 2000).
36. Id. at Articles 3,5,10, and 15; see also Medical Research Council of Canada, Natural Sciences and Engineering Research Council of Canada, Social Sciences and Humanities Research Council of Canada, Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (Ottawa: Public Works and Government Services Canada, 1998): at i.4.
37. Hall v. Hilburn, 466 So. 2d 856, 858 (MS 1985).
38. Crits v. Sylvester, 1 D.L.R. (2d.) 502, 508, (1956), aff'd [1956] S.C.R. 991.
39. Picard and Robertson, supra note 13, at 186.
40. Miller and Brody, supra note 1, at 3-5; see also Emanuel and Miller, supra note 7, at 915-19.
41. Giesen, supra note 12, at 50.
42. Id. at 193-195.
43. D. Giesen, "Civil Liability of Physicians for New Methods of Treatment and Experimentation: A Comparative Examination," Medical Law Review 3 (1995): 22-52, at 30.
44. E. H. Morreim, "Medical Malpractice Litigation and Malpractice Tort Doctrines: Courts on a Learning Curve," Houston Journal of Health Law and Policy 4 (2003): 1-92, at 92.
45. Professor Morreim published a further iteration of these arguments in "Litigation in Clinical Research: Malpractice Doctrines Versus Research Realities," Journal of Law, Medicine & Ethics 32 no. 3 (2004): 474-484 .
46. Id. at 34
47. Id.
48. Id. at 41.
49. Id. at 52.
50. Professor Morreim does allow in her discussion of fiduciary duties that there could be a relationship in a "pure research setting, in which the patient's only relationship with an investigator is as a research subject." Id. at 50-51. We believe that this could only be the case for "patients" who are not seeking or needing care, e.g., recruitment of persons to donate blood for a study unrelated to their own care. This situation is easily distinguishable from one in which a patient seeks advice and care from a physician who is an investigator and is recruited into a trial for a therapy addressing the patient's needs, including those with a placebo control.
51. B. Freedman, "Equipoise and the Ethics of Clinical Research,N. Engl. J. Med. 317 (1987): 141-45.
52. M. A. Rodwin, "Strains in the Fiduciary Metaphor: Divided Physician Loyalties and Obligations in a Changing Health Care System," American Journal of Law and Medicine 21 (1995): 241-57, at 243.
53. M. A. Hall, M. A. Bobinski and D. Orentlicher, Health Care Law and Ethics, 6th ed. (New York: Aspen Publishers, 2003): at 163-64; Lockett v. Goodill, 430 P.2d 589, 591 (WA, 1967); Moore v. Regents of the University of California, 793 P.2d 479 (1990); McInerney v. MacDonald (1992) 93 D.L.R. (4th) 415; Norberg v. Wynrib, (1992) 2 S.C.R. 227; Rodriguez v. British Columbia (Attorney General), (1993) 3 S.C.R. 519 .
54. Hall, Bobinski and Orentlicher, supra, at 163-64.
55. W. L. Prosser and P. Keeton, The Law of Torts, 5th ed. (St. Paul. MN: West Publishing Co, 1984).
56. M. J. Mehlman, "Fiduciary Contracting Limitations on Bargaining Between Patients and Health Care Providers," University of Pittsburgh Law Review 51 (1989-1990): 365-417, at 390.
57. Lockett v. Goodill, 430 P.2d 589, 591 (WA, 1967), as cited by Hall, Bobinski and Orenticher, supra note 35.
58. G. Robertson, Negligence and Malpractice, in J. Downie, T. Caulfield and C. Flood, eds., Canadian Health Law and Policy, 2nd ed. (Markham, Ontario: Butterworths, 2002): 91-109; Morreim, supra note 26, at 48; Moore v. Regents of the University of California, 793 P.2d 479, 483, 488 (1990). The Supreme Court of California has determined that an interest in research can conflict with an interest in the patient-participant's health and that a physician-investigator's eagerness to promote the advancement of science may result in riskier experimental treatments. The physician-investigator must disclose to a participant "any personal interests unrelated to the patient's health, whether research or economic, that may affect the physician's professional judgment." An action for conversion was dismissed even though the physician converted the patient-participant's blood products into a marketable commodity without consent. But the action for breach of the fiduciary duty to disclose financial interests in the research was accepted.
59. Glass and Lemmens, supra note 11.
60. Advisory Committee on Human Radiation Experiments, The Human Radiation Experiments (New York: Oxford University Press, 1996).
61. Gomez v. Comité exécutif du Conseil des médecins, dentistes et pharmaciens de l'Hôpital universitaire de Québec, (2001) J. Q. No. 5544. This was dealt with specifically by the Quebec Court of Appeal. At issue was a complaint filed with a university hospital medical disciplinary committee by the family of a man who died after participating in a research study on prostate cancer. The complainant argued that the patient/research subject had not received the proper standard of care, and that as a result of the negligence of the physicians involved in the research project, he had not been diagnosed in a timely fashion. The researchers argued that medical research escapes the traditional disciplinary rules of the profession and is only submitted to the authority of specialized research ethics committees. The Court stated that research is part of the mission of a university hospital; that in this type of research subjects could reasonably have expected diagnostic services and exceptional care; and that the terms "medical act" and "research" cannot be strictly separated. Discussing the latter, the Court points out that clinical research is an integral part of medicine, and is undertaken by physicians whose first professional duty is the protection of the health and well-being of individuals. Biomedical research and medical acts are not in opposition to one another, the Court states. In this court's view, research subjects can rightly expect that when research activities undertaken in medical research centers involve medical procedures, such as diagnostic services, the interventions they undergo will meet the standard of care physicians owe to their patients.
62. Giesen, supra note 12, at 595-96, § 251.
63. P. L. Gilbert, J. Harris et al, "Neuroleptic Withdrawal in Schizophrenic Patients," Archives of General Psychiatry 52 (1995): 173-88, at 173, 175, 182-85;
64. B. Spivak et al., "Neuroleptic Malignant Syndrome During Abrupt Reduction of Neuroleptic Treatment," Acta Psychiatrica Scandinavia 81 (1990): 168-69.
65. A. C. Viguera and R. J. Baldessarini et al, "Clinical Risk Following Abrupt and Gradual Withdrawal of Maintenance Neuroleptic Treatment," Archives of General Psychiatry 54 (1997): 49-55, at 49-54.
66. R. J. Baldessarini, A. C. Viguera, "Medication Removal and Research in Psychotic Disorders," Archives of General Psychiatry 55 (March, 1998): 281-82, at 282.
67. Gilbert, Harris et al., supra note 46, at 182.
68. R. J. Wyatt, "Neuroleptics and the Natural Course of Schizophrenia," Schizophrenia Bulletin 17 (1991): 325-51;
69. J. F. Greden and R. Tandon, "Long-Term Treatment for Lifetime Disorders? Archives of General Psychiatry 52 (1995): 197-99, at 198.
70. Greden and Tandon, supra, at 198.
71. Viguera, and Baldessarini supra note 47, at 51.
72. Greden and Tandon, supra note 51, at 198; C. Elliott and C. Weijer, "Cruel and Unusual Treatment," Saturday Night 110, no. 10 (1995): 31-34, at 32.
73. Greden and Tandon, supra note 51, at 198. There is anecdotal evidence that details such as relapse rates have been kept out of the informed consent process because they were "overly frightening." Put another way, such details might discourage enrollment in RCTs. The altruism that supposedly motivates some psychiatric patients to enroll in placebo-controlled trials may not endure an understanding of the potential for adverse effects. See also D. King, "Debatable Forms of Consent," The Boston Globe, November 16, 1998, at A01. King quotes Wesley Acorn, then president of the national consumer council for the U.S. National Alliance for the Mentally Ill, as saying, "Do you think people say 'Gee, I'll sign up for more suffering. Many of us suffer enough on our own.'"
74. Baldessarini and Viguera, supra note 46, at 282; Viguera, Baldessarini et al., supra note 45, at 54; R. J. Baldessarini, "Risks and Implications of Interrupting Maintenance Psychotic Drug Therapy," Psychotherapy and Psychosomatik 63 (1995): 137-41, at 139;
75. D. V. Jeste, P. L. Gilbert et al., "Considering Neuroleptic Maintenance and Taper on a Continuum," Archives of General Psychiatry 52 (1995): 209-12, at 210;
76. R. Wyatt, "Risks of Withdrawing Antipsychotic Medications," Archives of General Psychiatry, 52 (1995): 205-08, at 207.
77. A. C. Viguera, R. J. Baldessarini et al., supra note 47, at 50.
78. W. T. Carpenter and R. Coney, "Sense and Nonsense: An Essay on Schizophrenia Research Ethics," Scizophrenia Research 35 (1999): 219-25, at 222.
79. W. T. Carpenter, P. S. Appelbaum and R. J. Levine, "The Declaration of Helsinki and Clinical Trials: A Focus on Placebo-Controled Trials in Schizophrenia," American Journal of Psychiatry 160 (2003): 356-62, at 359.
80. J. R. Geddes, S. M. Carey, C. Davis and T. A. Furukawa et al., "Relapse Prevention with Antidepressant Drug Treatment in Depressive Disorders: A Systematic Review," The Lancet 361 (2003): 653-61.
81. T. Pincus and L. F. Callahan, "The 'Side Effects' of Rheumatoid Arthritis: Joint Destruction, Disability and Early Mortality," British Journal of Rheumatology 32, suppl. 1 (1993): 28-37;
82. F. Wolfe and M. A. Cathey, "The Assessment and Prediction of Functional Disability in Rheumatoid Arthritis," Journal of Rheumatology 18 (1991): 1298-1306;
83. P. A. Reilly, J. A. Cosh, P. J. Maddison, J. J. Rasker and A. Silman, "Mortality and Survival in Rheumatoid Arthritis: a 25 Year Prospective Study of 100 Patients," Annals of the Rheumatic Diseases 49 (1990): 363-69.
84. P. Emery, "The Roche Rheumatology Prize Lecture: The Optimal Management of Early Rheumatoid Disease: The Key to Preventing Disability," British Journal of Rheumatology 33 (1994): 765-68;
85. T. Pincus and L. E. Callahan, "How Many Types of Patients Meet Classification Criteria for Rheumatoid Arthritis?" Rheumatology 21 (1994): 1385-89.
86. J. F. Fries, C. A. Williams, D. Morfeld, G. Singh and J. Sibley, "Reduction in Long-Term Disability in Patients with Rheumatoid Arthritis by Disease-Modifying Anti-rheumatic Drug-Based Treatment Strategies," Arthritis & Rheumatism 39 (1996): 616-22;
87. P. L. Van Riel, D. M. van der Heijde, I. H. Nuver-Zwart and L. B. van de Putte, "Radiographic Progression in Rheumatoid Arthritis: Results of 3 Comparative Trials," Journal of Rheumatology 22 (1995): 1797-99;
88. O. Forre, "Radiologic Evidence of Disease Modification in Rheumatoid Arthritis Patients Treated with Cyclosporine: Results of a 48-week Multicenter Study Comparing Low-Dose Cyclosporine with Placebo: Norwegian Arthritis Study Group," Arthritis & Rheumatism 37 (1994): 1506-12.
89. C. M. Stern and T. Pincus, "Placebo-Controlled Studies in Rheumatoid Arthritis: Ethical Issues," The Lancet 353 (1999): 400-03, at 400.
90. Id; Temple and Ellenberg, supra note 5.
91. T. Lemmens, D. Sprumont, H. Nys, J. Singh, and K. C. Glass, "CIOMS' Placebo Rule and the Promotion of Negligent Medical Practice," European Journal of Health Law 11 (2004): 153-74, at 163.
92. Neufield v. McQuitty, 18 AR 271(1979); Halushka v. University of Saskatchewan 53 D.L.R. (2d) 436 (1965); Cryderman v. Ringrose, 3 W.W.R. 481 (Alta. CA, 1977); Coughlin v. Kuntz 17 B.C.L.R. 365 (1987); Civil Code of Quebec, S.Q., 1991, Articles 1474, 1477; Grimes v. Kennedy Kreiger Institute, 782 A.2d 807, 834 (2001); Gomez v. Comité exécutif du Conseil des médecins, dentistes et pharmaciens de l'Hôpital universitaire de Québec, supra note 43.
93. T. Lemmens et al, supra note 65.
94. J. Menikov, Law and Bioethics: An Introduction (Washington, DC: Georgetown University Press, 2001).
95. Miller and Brody, supra note 1.
96. Miller, supra note 2.
97. Freedman, supra note 34.
98. Id.
99. B. Freedman, "Ethics and Placebo-Controlled Thrombolytic Trials: The Future," Coronary Artery Disease 2, no. 7 (1991): 849-52, at 850.
100. C. Weijer, "When Argument Fails," American Journal of Bioethics 2 (2002): 10-11, at 10.
101. The National Placebo Working Committee Report on the Appropriate Use of Placebo in Clinical Trials (Ottawa: Health Canada and Canadian Institutes of Health Research, 2004).
102. B. Freedman, K. C. Glass and C. Weijer supra note 7; K. C. Glass and D. Waring supra note 7, at 26. M. Oberman, "Mothers and Doctor's Orders: Unmasking the Doctor's Fiduciary Role in Maternal-Fetal Conflicts," Northwestern University Law Review 94 (2000): 451-501, at 459.